Renata Pugliese

FREQUENCY OF CONCURRENT AUTOIMMUNE DISORDERS IN PATIENTS WITH AUTOIMMUNE HEPATITIS: EFFECT OF AGE, GENDER, AND GENETIC BACKGROUND

Background Concurrent autoimmune disorders (CAIDs) have been shown to occur in 22% to 34% of the patients with autoimmune hepatitis (AIH). Their presence has been linked to female gender, older age, and to certain HLA antigens, namely HLA-A11, DRB1*04, and DRB4*01. Aims To assess the frequency and nature of CAID in Brazilian patients with AIH types 1 (AIH-1) and 2 (AIH-2) and to investigate the influence of age, gender, and genetic background in their occurrence. Patients and Methods The presence and nature of CAID was studied in 143 patients [117 females, median age 11 (1.3 to 69)] with AIH-1 (n=125) and AIH-2 (n=28). HLA typing and tumor necrosis factor α gene promoter and exon 1 cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms were determined by polymerase chain reaction-based techniques. Results The frequency of CAID was similar in patients with AIH-1 (14%) and AIH-2 (18%), but their nature was shown to vary. Arthritis was seen in half of the patients (n=8) with CAID and AIH-1 and in none of those with AIH-2. Subjects with AIH-1 and CAID were shown to be older [24 (1.3 to 61) vs. 11 (1.3 to 69) y, P=0.02] and to have more often circulating antinuclear antibody (76% vs. 40%, P=0.008) and less frequently antiactin antibodies (33% vs. 75%, P=0.008) when compared with their counterparts without CAID. No particular HLA-DR and DQ alleles, as well as tumor necrosis factor α and CTLA-4 genotypes, were associated with CAID. Conclusions The nature, but not the frequency, of CAID was shown to vary in AIH-1 and AIH-2. In subjects with AIH-1, CAID was linked to older subjects and to the presence of antinuclear antibody. No predisposition to CAID was associated to HLA-DRB1*04 or DDB4*01 alleles. The observed lower frequency of CAID could be attributed to the lower age of disease onset in Brazilians and to differences in HLA-encoded susceptibility to AIH-1 observed in South America.

Four hundred thirty consecutive pediatric living donor liver transplants: Variables associated with posttransplant patient and graft survival

The availability of living donors allows transplant teams to indicate living donor liver transplantation (LDLT) early in the course of liver disease before the occurrence of life‐threatening complications. Late referral to transplant centers is still a problem and can compromise the success of the procedure. The aim of this study was to examine the perioperative factors associated with patient and graft survival for 430 consecutive pediatric LDLT procedures at Sirio‐Libanes Hospital/A. C. Camargo Hospital (São Paulo, Brazil) between October 1995 and April 2011. The studied pretransplant variables included the following: recipient age and body weight, Pediatric End‐Stage Liver Disease score, z score for height/age, bilirubin, albumin, international normalized ratio, hemoglobin, sodium, presence of ascites, and previous surgery. The analyzed technical aspects included the graft‐to‐recipient weight ratio and the use of vascular grafts for portal vein reconstruction. In addition, the occurrence of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT), and biliary complications was also analyzed. The liver grafts included 348 left lateral segments, 5 monosegments, 51 left lobes, and 9 right lobes. In a univariate analysis, an age < 12 months, a low body weight (≤10 kg), malnutrition, hyperbilirubinemia, and HAT were associated with decreased patient and graft survival after LDLT. In a multivariate analysis, a body weight ≤ 10 kg and HAT were significantly associated with decreased patient and graft survival. The use of vascular grafts significantly increased the occurrence of PVT. In conclusion, a low body weight (≤10 kg) and the occurrence of HAT independently determined worse patient and graft survival in this large cohort of pediatric LDLT patients. Liver Transpl, 2012.

Modified Pediatric End-Stage Liver Disease Scoring System and Pediatric Liver Transplantation in Brazil

The Pediatric End‐Stage Liver Disease (PELD) scoring system is a formula developed to provide a continuous numerical assessment of the risk of death in order to allocate livers to children in need of transplantation. The PELD scoring system was introduced in Brazil in July 2006. An important change was made in the system: the final number for listing patients less than 12 years old for transplantation was the calculated PELD score multiplied by 3. The consequences of this allocation policy were analyzed in 2 ways in this research: nationally and in the state of São Paulo (SP State). In the analysis of the national data, a comparison of the pre‐PELD era (July 2003 to July 2006) and the post‐PELD era (August 2006 to April 2009) showed that the total number of pediatric transplants for children under 12 years of age decreased 7%. Regionally, in SP State, there was a 62% increase in the number of deceased donor liver transplantation procedures for the pediatric population after the introduction of the modified PELD system. There was also a 6.1‐fold increase in split liver transplantation as well as a statistically significant decrease in the time on the waiting list (P < 0.001). In conclusion, changing the allocation policy in Brazil in order to benefit pediatric patients on the waiting list had different results according to analyses of national and regional data. A significant increase in deceased donor liver transplantation/split liver transplantation and a shorter time on the waiting list were observed in SP State. The modified PELD scoring system is simple and optimizes the utilization of deceased donor liver grafts in centers performing pediatric transplants. Liver Transpl, 2010.

Living donor liver transplantation for children in Brazil weighing less than 10 kilograms

Infants with end‐stage liver disease represent a treatment challenge. Living donor liver transplantation (LDLT) is the only option for timely liver transplantation in many areas of the world, adding to the technical difficulties of the procedure. Factors that affect morbidity and mortality can now be determined, which opens a new era for improvement. We have accumulated an 11‐year experience with LDLT for children weighing <10 kg. From October 1995 to October 2006, a total of 222 LDLT in patients <18 years of age were performed; 129 primary LDLT and 7 retransplants (4 LDLT and 3 deceased donor grafts) were performed in 129 infants weighing <10 kg. Forty‐seven patients received grafts with graft‐to‐recipient weight ratio (GRWR) of >4%. Two patients received monosegmental grafts, and 2 patients underwent delayed abdominal wall closure. Portal vein thrombosis occurred in 5.4% of the patients, hepatic artery thrombosis in 3.1%, and both in 1.5%. Among several variables studied, only the bilirubin level at the time of transplantation was associated with increased risk of death (P = 0.009). Grafts with GRWR >4% had no negative effect on patient survival. There were 7 retransplants, and 4 patients received a second parental LDLT. Patient survival rates at 1, 3, and 10 years after transplantation were 88.8%, 84.7%, and 82% for all children, and 87.5%, 84.9%, and 84.9% for infants weighing <10 kg. LDLT has results comparable to other modalities of liver transplantation in infants. Monosegment grafts were rarely required in this series, although they may be necessary in patients with lower body weight. Liver Transpl 13:1153–1158, 2007.

Diagnosis and management of biliary complications in pediatric living donor liver transplant recipients

The incidence of biliary complications (BCs) after living donor liver transplantation (LDLT) can reach 40%. Published data on the pediatric population are limited, and treatment protocols vary. Our aim was to describe the clinical scenario for BCs and treatment approaches after LDLT. Between October 1995 and December 2012, 489 pediatric LDLT procedures were performed. BCs developed in 71 patients (14.5%). Biliary strictures (BSs) developed in 45 (9.2%) patients, and bile leaks (BLs) developed in 33 patients (6.7%). The BL diagnosis was clinical in all cases, and 69.7% of the patients underwent surgery. Nearly half of the BS cases had clinical features or suggestive ultrasound findings. Liver biopsy findings suggested BSs in 51.7%. Percutaneous transhepatic cholangiography was performed in 95.6% of the BS patients. The success rate was 77% [mean number of percutaneous biliary interventions (PBIs) = 3.9 ± 1.98, median drainage time = 8 months]. In conclusion, BL patients can be managed with conservative therapy, even though most of these patients will ultimately be treated with surgery. Diagnosing a BS requires a high degree of clinical suspicion because the available resources for its identification can fail in up to 50% of cases. A higher number of PBIs and the use of a drainage catheter for a longer time may be required to achieve better results with this technique. Liver Transpl 20:882‐892, 2014.

Ascites and serum sodium are markers of increased waiting list mortality in children with chronic liver failure

Ascites is the most common complication of cirrhosis and in adults it is associated with 50% mortality at 5 years if patients do not receive a liver transplant. The occurrence of hyponatremia in these patients has been associated with increased mortality on the waiting list. The importance of serum sodium levels and the presence of ascites in the pediatric setting remain to be clarified. A retrospective analysis of pediatric patients with cirrhosis on the transplant list was carried out between October 2000 and February 2012. The primary objective of this study was to evaluate the association of pretransplant variables with mortality within 90 days following the inclusion of patients on the waiting list. In all, 522 patients were included in the study; 345 (66%) patients were under 1 year of age; 208 (40%) of the children presented ascites. A multivariate Cox proportional hazards analysis was conducted and total bilirubin (P < 0.001, hazard ratio [HR] = 2.09, 95% confidence interval [CI] = 1.35‐3.21), international normalized ratio (INR) (P < 0.001, HR = 9.83, 95% CI = 4.51‐21.45), serum sodium levels (P = 0.03, HR = 0.96, 95% CI = 0.92‐0.99), ascites (P = 0.001, HR = 2.59, 95% CI = 1.44‐4.64), and categorized age (0‐1 versus ≥1 year old) (P = 0.025, HR = 2.33, 95% CI = 1.11‐4.86) were independently associated with risk of death in 90 days. Malnutrition (Z score height/age, weight/age) and serum albumin (pediatric endstage liver disease [PELD] formula) were not included in the final model. Conclusion: The presence of ascites and serum sodium levels are important variables associated with decreased patient survival while candidates wait for a liver graft. Multicenter studies are necessary to validate these findings in order to improve current allocation policies based on the PELD score. (Hepatology 2014;59:1964–1971)

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patients mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

Impact of Kasai portoenterostomy on liver transplantation outcomes: A retrospective cohort study of 347 children with biliary atresia

Biliary atresia (BA) is the main diagnosis leading to liver transplantation (LT) in children. When diagnosed early in life, a Kasai portoenterostomy (Kasai‐PE) can prevent or postpone LT. Instances of previous operations can result in difficulties during the LT. We hypothesized that a previous Kasai‐PE could affect LT outcomes. A retrospective cohort study of 347 BA patients submitted to LT between 1995 and 2013 at Hospital Sírio‐Libanês and A. C. Camargo Cancer Center was conducted. Patients were divided into those with a previous Kasai portoenterostomy early failure (K‐EF), Kasai portoenterostomy late failure (K‐LF), and those with no Kasai portoenterostomy (No‐K). Primary outcomes were patient and graft survival. A total of 94 (27.1%) patients had a K‐EF, 115 (33.1%) had a K‐LF, and 138 (39.8%) had No‐K before LT. Children in the K‐LF group were older and had lower Pediatric End‐Stage Liver Disease (PELD) scores. Patients in both K‐EF and K‐LF groups had more post‐LT biliary complications. After Cox‐multivariate analysis adjusting for confounding factors to determine the influence of Kasai‐PE on patient and graft survival, the K‐LF group had an 84% less probability of dying and a 55% less chance to undergo retransplantation. The K‐LF group had a protective effect on posttransplant patient and graft survival. When properly performed, the Kasai procedure can postpone LT and positively affect outcomes. Having a K‐EF and having not performed a Kasai‐PE had the same effect in patient and graft survival; however, a previous Kasai‐PE can increase post‐LT complications as biliary complications and bowel perforations. Liver Transpl 21:922‐927, 2015.

Schistosoma mansoni infection in the liver graft: The impact on donor and recipient outcomes after transplantation.

The increasing number of transplants performed each year has led to the identification of unusual diseases in liver grafts from asymptomatic donors that were unrecognized before liver transplantation. Here we report our experience with patients who received liver grafts infected with schistosomiasis. From September 1991 to August 2010, 482 pediatric liver transplants were performed at A. C. Camargo Hospital/Sírio‐Libanês Hospital (São Paulo, Brazil). For the identification of Schistosoma mansoni infections, pathology slides for the recipients were reviewed; these included postreperfusion and follow‐up liver biopsy samples. We were able to identify 6 cases of schistosomiasis transmitted through infected grafts (5 of these grafts were from living donors). All living donors were confirmed to have normal liver chemistries, negative fecal tests for parasitic diseases, and normal abdominal ultrasound findings. Liver biopsy was not performed before transplantation. In all cases, features of schistosomiasis were absent in the liver explants. The living donors were treated with praziquantel and were taught to avoid risk factors for reinfection. No specific treatment for schistosomiasis was given to the recipients. There were no perioperative deaths, but 2 recipients died after living donor liver transplantation (LDLT) because of Kaposis sarcoma and non‐Hodgkins lymphoma. In conclusion, using liver grafts infected with S. mansoni eggs did not compromise the results of LDLT in this pediatric cohort. Because of the parasites life cycle and the therapeutic target of praziquantel, only donors should be treated for the infection. Three years of follow‐up showed an uneventful recovery for the living donors. Liver Transpl 17:1299–1303, 2011.

Left Lateral Segmentectomy for Pediatric Live-Donor Liver Transplantation : Special Attention to Segment IV Complications

Background. During left lateral segmentectomy for live-donor liver transplant, the vascular inflow to segment IV can be compromised. An area of ischemia can be seen intraoperatively and further segment IV resection may be needed to prevent necrosis and abscess formation. Methods. From July 1995 to February 2007, 324 consecutive living donor liver transplantations were performed at Hospital A. C. Camargo and Hospital Sirio-Libanes, Sao Paulo, Brazil. Two hundred eleven left lateral segments were transplanted in this period. Data on 204 left lateral segments donors were available for this analysis. Results. There were 108 female and 96 male donors. Median age was 29 years (range, 16–48 years). Median follow-up time was 2.2 years (range, 2 months–11.8 years). Median intensive care unit stay was 1 day (range, 1–3 days), and median hospital stay was 5 days (range, 4–47 days). Postoperative complications were encountered in 39 donors (19.1%). Partial segment IV resection on the course of the primary surgery due to parenchyma discoloration was required in 107 cases (52.5%). Ten patients (4.9%) developed segment IV necrosis or abscesses, although four of them had had segment IVB resection intraoperatively. Segment IV necrosis or abscess significantly increased hospital stay and the number of readmissions, from 5.5±3.5 days to 8.4±3.7 days (P=0.012) and from 6 of 194 (3%) to 5 of 10 (50%) (P=0.001), respectively. Conclusions. Middle hepatic segment abscess or necrosis was the most frequent complication after left lateral segmentectomy (4.9%). Objective intraoperative strategies need to be developed to evaluate middle hepatic segment ischemia to identify and treat patients at higher risk.