Neuropsychological profile in tuberous sclerosis complex: a study of clinical and cognitive variables in a cohort from Brazil.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with a wide clinical, cognitive, and behavioral expressivity. OBJECTIVE: To assess the neuropsychological profile of individuals clinically diagnosed with TSC and the factors that could significantly impact their cognitive development. METHODS: A total of 62 individuals with ages ranging from 3 to 38 years were followed up in a tertiary attention hospital in Southern Brazil, and they were assessed using a standard battery and the Vineland Adaptive Behavior Scales, when intellectual disability was observed. RESULTS: History of epilepsy was found in 56 participants (90.3%), and 31 (50%) presented an intellectual disability. Among the other half of TSC individuals without intellectual disability, 8 (12.9%) presented borderline classification, 20 (32.2%) presented average scores, and 3 (4.8%) were above average. In total, 17 participants (27.4%) fulfilled the diagnostic criteria for autism spectrum disorder. The results of the multiple linear regression analysis suggested that seizures, age at diagnosis, visual perception, and general attention significantly impact cognitive performance indexes. CONCLUSION: The present study suggests that the occurrence of epileptic seizures and older age at diagnosis contribute to higher impairment in the domains of cognitive development, underlining the importance of early diagnosis and the prevention of epileptic seizures or their rapid control. The development of attentional skills, visual perception, and executive functions must be followed up.

ANTECEDENTES: O complexo da esclerose tuberosa (CET) é uma doença genética autossômica dominante com ampla expressividade clínica, cognitiva e comportamental. OBJETIVO: Avaliar o perfil neuropsicológico de indivíduos com diagnóstico clínico de CET e os fatores que poderiam impactar significativamente o seu desenvolvimento cognitivo. MéTODOS: Ao todo, 62 indivíduos com idades entre 3 e 38 anos foram acompanhados em um hospital terciário do Sul do Brasil e avaliados por meio de uma bateria padrão e das Escalas de Comportamento Adaptativo Vineland, quando observada deficiência intelectual. RESULTADOS: Encontrou-se histórico de epilepsia em 56 participantes (90,3%) e de deficiência intelectual em 31 (50%). Quanto à outra metade dos indivíduos com CET sem deficiência intelectual, 8 (12,9%) apresentaram classificação limítrofe, 20 (32,2%) apresentaram pontuações médias e 3 (4,8%) estavam acima da média. No total, 17 participantes (27,4%) preenchiam os critérios diagnósticos para o transtorno do espectro autista. Os resultados da análise de regressão linear múltipla sugeriram que as crises epilépticas, a idade ao diagnóstico, a percepção visual e a atenção geral impactam significativamente os índices de desempenho cognitivo. CONCLUSãO: Este estudo sugere que a ocorrência de crises epilépticas e a maior idade ao diagnóstico contribuem para um maior comprometimento nos domínios do desenvolvimento cognitivo, e destaca-se a importância do diagnóstico precoce e da prevenção das crises epilépticas ou do seu rápido controle. O desenvolvimento de habilidades de atenção, percepção visual e funções executivas deve ser acompanhado.

Liver Transplantation for Benign Massive Hepatomegaly: Results From a Single Center and Contribution of the Left-to-Right Piggyback Approach.

INTRODUCTION: Polycystic liver disease and giant hepatic hemangioma may present with severe symptom burden and indicate orthotopic liver transplantation. The left-to-right piggyback approach is a useful technique for performing total hepatectomy of enlarged livers. OBJECTIVE: The purpose of this study is to analyze the results of liver transplantation in patients with benign massive hepatomegaly. METHODS: This is a single-center retrospective study involving all adult patients who underwent liver transplantation due to benign massive hepatomegaly from January 2002 to June 2023. RESULTS: A total of 22 patients underwent liver transplantation (21 cases of polycystic live disease and 1 case of giant hepatic hemangioma). During the same time, there were 2075 transplants; therefore, benign massive hepatomegaly accounted for 1.06% of cases. Most patients (59.09%) were transplanted using the left-to-right piggyback technique. Seven patients had previous attempted treatment of hepatic cysts. Another patient previously underwent bilateral nephrectomy and living-donor kidney transplantation. Among these patients, in 5 cases there were massive abdominal adhesions with increased bleeding. Four of these 8 patients died in the very early perioperative period. In comparison to patients without previous cysts manipulation, massive adhesions and perioperative death were significantly higher in those cases (62.5 vs 0%, P = .002 and 50% vs 0%, P = .004, respectively). CONCLUSION: Liver transplantation due to polycystic liver disease and giant hemangioma is a rare event. Total hepatectomy is challenging due to the enlarged native liver. The left-to-right piggyback technique is useful, because it avoids vena cava twisting and avulsion of its branches. Massive adhesions due to previous cysts manipulation may lead to increased bleeding, being a risk factor for mortality.

Retransplantation for Late Hepatic Artery Thrombosis: Results from a Single Center.

BACKGROUND: Hepatic artery thrombosis is the most common vascular complication of liver transplantation. When occurring late in the postoperative course, it may have no clinical repercussions, and conservative treatment may be implemented. Some patients, however, will develop severe biliary complications due to ischemic cholangiopathy and require retransplantation. The aim of this study is to report the outcomes of retransplantation in this population. METHODS: This is a single-center retrospective study involving all adult patients who underwent liver retransplantation due to late hepatic artery thrombosis from January/2010 to December/2022. RESULTS: During the study period, 1378 liver transplants were performed in our center; 147 were retransplantations, with 13 cases of late hepatic artery thrombosis (0.94%). All had symptomatic ischemic cholangiopathy. Twelve of them had already presented previous cholangitis, bilomas, or liver abscesses and had undergone biliary stenting or percutaneous drainage. The median time between the first liver transplant and late hepatic artery thrombosis diagnosis and between this diagnosis and retransplantation were 73 and 50 days, respectively. Arterial reconstruction using splenic artery, celiac trunk, or arterial conduit from the aorta was performed in 7 cases, whereas biliary reconstruction was mostly done with choledochojejunostomy (n = 8). There were 4 perioperative deaths, 2 due to primary non-function and 2 due to refractory shock after exceedingly complex retransplants. CONCLUSION: Liver retransplantation due to late hepatic artery thrombosis is a rare condition that should be offered to patients who develop severe biliary complications and recurrent infections. It is nonetheless a challenging procedure associated with significant perioperative mortality.

Liver Transplantation for Adenomatosis: A Single-Center Experience.

BACKGROUND: Liver adenomatosis is characterized by multiple adenomas diffusely distributed throughout the liver parenchyma. Studies addressing liver transplantation for those cases are scarce, and the criteria used to indicate transplantation are still debatable. OBJECTIVE: To report a single-center experience of liver transplantation for diffuse adenomatosis. METHODS: Single-center retrospective study involving all adult patients who underwent liver transplantation due to adenomatosis from January/2010 to June/2023. RESULTS: A total of 13 patients were identified, corresponding to 0.89% of liver transplants performed during the study period. The mean age was 33 ± 6.55 years, and most of them were female (n = 9, 69.23%). There were 12 transplants with deceased donors and 1 with a right lobe from a living donor. The most frequent reason to preclude liver resection was multiple and large unresectable adenomas in patients without previous liver disease (n = 8, 61.58%), followed by underlying liver disease (Abernethy Malformation, n = 3, 23.07%) and recurrence after liver resection (n = 2, 15.38%). The indications for liver transplantation were high risk of malignant transformation (n = 7, 53.84%), increasing size and number of nodules (n = 3, 23.07%), confirmed malignant transformation (n = 2, 15.38%), and hemorrhage (n = 2, 15.38%). There was 1 perioperative death due to primary non-function. Another patient died during follow-up because of COVID-19. CONCLUSION: Liver adenomatosis is a rare indication for liver transplantation, with acceptable post-transplant outcomes. Unresectable adenomas with high-risk or confirmed malignant transformation are the main indications for transplant. Reasons for unresectability involve underlying liver disease, multiple and large high-risk nodules, and recurrence after previous resection.

GJB2 c.35del variant up-regulates GJA1 gene expression and affects differentiation of human stem cells.

Pathogenic DNA alterations in GJB2 are present in nearly half of non-syndromic hearing loss cases with autosomal recessive inheritance. The most frequent variant in GJB2 causing non-syndromic hearing loss is the frameshifting c.35del. GJB2 encodes Cx26, a protein of the connexin family that assembles hemichannels and gap junctions. The expression of paralogous proteins is believed to compensate for the loss of function of specific connexins. As Cx26 has been involved in cell differentiation in distinct tissues, we employed stem cells derived from human exfoliated deciduous teeth (SHEDs), homozygous for the c.35del variant, to assess GJB2 roles in stem cell differentiation and the relationship between its loss of function and the expression of paralogous genes. Primary SHED cultures from patients and control individuals were compared. SHEDs from patients had significantly less GJB2 mRNA and increased amount of GJA1 (Cx43), but not GJB6 (Cx30) or GJB3 (Cx31) mRNA. In addition, they presented higher induced differentiation to adipocytes and osteocytes but lower chondrocyte differentiation. Our results suggest that GJA1 increased expression may be involved in functional compensation for GJB2 loss of function in human stem cells, and it may explain changes in differentiation properties observed in SHEDs with and without the c.35del variant.

A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC).

BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous syndrome with variable phenotypes. Recent updates of TSC diagnostic criteria reaffirmed the defined genetic diagnostic criterion as the finding of a pathogenic DNA alteration in either TSC1 or TSC2 genes. It also slightly modified definite clinical diagnostic criteria. TSC-associated skin lesions in infancy are important clinical signs to select individuals with possible TSC for a closer clinical follow-up and genetic testing. OBJECTIVE: To raise awareness of the updated TSC diagnosis criteria; to assess the frequency of skin lesions in TSC patients as well as the first dermatological presentation; and to associate the findings with either TSC1 or TSC2 mutations. METHODS: Observational cross-sectional study. Clinical and genetic data were retrospectively collected from 37 TSC patients from a Brazilian University Hospital. Patients with skin signs were examined and prospectively assessed for 12 months. RESULTS: The earliest cutaneous lesions were hypomelanotic macules, which together with angiofibromas were the most frequent dermatological lesions. The total pathogenic DNA alteration ratio between TSC2 and TSC1 genes was 8:1. The frequency of a TSC2 pathogenic variant was 10-fold greater in the presence of ungual fibromas. STUDY LIMITATIONS: Small sample and a limited number of patients with TSC1 pathogenic variants. CONCLUSION: Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders.

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.

Understanding the Elevated Lethality of COVID-19 in Liver Transplant Recipients: Does Immunosuppression Management Matter? Results from a Brazilian Multicentric Historical Cohort.

BACKGROUND: Infections by SARS-CoV-2 in liver transplant recipients (LT) patients are of particular concern, notably due to perceived added risks related to immunosuppression and comorbidity burden. Current literature on this topic often relies on small, non-standardized, and geographically limited studies. This manuscript describes COVID-19 presentations and causes for elevated mortality in a large cohort of LT recipients. METHODS: This study was designed as a multicentric historical cohort, including LT recipient patients with COVID-19 in 25 study centers, with the primary endpoint being COVID-related death. We also collected demographic, clinical, and laboratory data regarding presentation and disease progression. RESULTS: Two hundred and thirty-four cases were included. The study population was predominantly male and White and had a median age of 60 years. The median time from transplantation was 2.6 years (IQR 1-6). Most patients had at least one comorbidity (189, 80.8%). Patient age (P = .04), dyspnea (P < .001), intensive care unit admission (P < .001), and mechanical ventilation (P < .001) were associated with increased mortality. Modifications of immunosuppressive therapy (P < .001), specifically the suspension of tacrolimus, maintained significance in multivariable analysis. CONCLUSIONS: Attention to risk factors and the individualization of patient care, especially regarding immunosuppression management, is crucial for delivering more precise interventions to these individuals.

Clinical Validation of a Novel Scoring System Based on Donor and Recipient Risk Factors for Predicting Outcomes in Liver Transplantation.

BACKGROUND Adequate donor and recipient matching in liver transplantation is crucial to improve patient survival. Our objective was to propose and validate a new model for predicting outcomes using donor and recipient scoring criteria. MATERIAL AND METHODS We retrospectively analyzed data of all patients (n=932) who underwent liver transplantation (n=1106) from January 2006 to December 2018. For score standardization, 30% (n=280) of patients were randomly selected for analysis and divided into 3 categories: ≤4 points, 5 to 8 points, and >8 points. Scoring system validation was performed on a dataset with 70% (n=652) of the patients. RESULTS Survival of the stratified group (30%) was significant (P<0.001). Scores of 4 to 8 points presented lower risk of death (1.74 [CI 0.97-3.13; P=0.062]), while >8 points presented higher risk (2.74 [CI 1.36-5.57; P=0.005]). In the validation score (70%), global survival was significant (P<0.0016); patients with scores of 4 to 8 points had lower risk of death (1.16 [CI 1.16-2.38; P=0.005]); and scores >8 points (2.22 [CI 1.40-3.50; P<0.001]), retransplant, fulminant hepatitis, previous large abdominal/biliary tree surgery, MELD score, and serum creatinine before liver transplantation >1.5 mg/dL (P<0.05) presented higher risk. Individual recipient factors with 4 to 8 points had a lower risk of death (2.29 [CI 1.82-2.87; P<0.0001]) than those with scores >8 points (4.02 [CI 2.22-7.26; P<0.0001]). CONCLUSIONS A novel prognostic-based scoring system using donor and recipient characteristics was proposed and clinically validated. Two-factor scoring indicated the superiority of the predictability outcome and improved prediction of higher mortality.

COST EFFECTIVENESS OF USING TERLIPRESSIN TO TREAT HEPATORENAL SYNDROME.

BACKGROUND: Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. OBJECTIVE: To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. METHODS: Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. RESULTS: After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. CONCLUSION: A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

COVID-19 Pandemic Impact on Liver Donation in the Largest Brazilian Transplantation Center.

BACKGROUND: COVID-19 has spread worldwide and has become a public health emergency and a pandemic of international concern. The solid organ donation system was no different. This study aimed to investigate the effect of COVID-19 on the liver transplant (LT) system in Brazilian territory. METHODS: We retrospectively reviewed all liver donor records allocated in São Paulo State, Brazil, 1 year before and 1 year during the COVID-19 pandemic. We defined the pre-COVID-19 (PRE) period as between April 2019 and April 2020 and the post-COVID-19 (POST) period as between April 2020 and April 2021. Moreover, we compared LT performed in our institution during these periods. To evaluate outcomes, we compared 30-day survival after LT. RESULTS: In the PRE period, 1452 livers were offered for donation in São Paulo State and other Brazilian territories. Of these, 592 were used in LT. In the POST period, 1314 livers were offered for donation, but only 477 were used in LT. Organ refusal was higher in the POST period (P < .05). Our center performed 127 and 156 LTs in these periods, respectively, and an increase above 20% was significant (P = .039). There was no difference in 30-day survival between the periods (87.2% vs 87.9%, P > .5, respectively). CONCLUSIONS: The COVID-19 pandemic harmed potential and allocated donors and LTs performed. However, it is possible to maintain the LT volume of a transplant center without compromising survival outcomes through preventive strategies against COVID-19 propagation.

Septuagenarian Donors and Recipients in Deceased Donor Liver Transplantation: A Brazilian Single Center Experience and Literature Review.

BACKGROUND: The number of elderly patients who have end-stage liver disease and require liver transplantation has dramatically increased. On the other hand, liver grafts from elderly donors have been offered more frequently for transplantation. The present study aims to analyze the results of liver transplants performed with donors and recipients aged ≥70 years. METHODS: We performed a single-center retrospective study of deceased donors liver transplants that involved recipients aged ≥7070 years or recipients who received grafts from donors aged ≥70 years from 2011 to 2021. A literature review on the results of liver transplantation in elderly recipients was also performed. RESULTS: Thirty septuagenarian recipients were included; their overall 1- and 5-years survival was 80% and 76.6%, respectively. The prevalence of recipients aged ≥70 years in our department was 2.65%. Twenty recipients received grafts form septuagenarian donors; their overall 1- and 5-years survival was 75%. The prevalence of donors aged ≥70 years in our department was 1%. In the literature review, 17 articles were analyzed. The 5-years survival of recipients aged ≥70 years ranged from 47.1% to 78.5%. CONCLUSIONS: Septuagenarian recipients and patients who received grafts from elderly brain-dead donors present adequate overall survival after liver transplantation. Optimized donor-recipient matching is paramount for achieving good outcomes. The combination of high-risk donors with septuagenarian recipients should be avoided as well as using grafts of elderly donors that present others risk factors. Thus, the age of the donor or recipient alone cannot be considered an absolute contraindication for liver transplantation.

Fmr1 exon 14 skipping in late embryonic development of the rat forebrain.

BACKGROUND: Fragile X syndrome, the major cause of inherited intellectual disability among men, is due to deficiency of the synaptic functional regulator FMR1 protein (FMRP), encoded by the FMRP translational regulator 1 (FMR1) gene. FMR1 alternative splicing produces distinct transcripts that may consequently impact FMRP functional roles. In transcripts without exon 14 the translational reading frame is shifted. For deepening current knowledge of the differential expression of Fmr1 exon 14 along the rat nervous system development, we conducted a descriptive study employing quantitative RT-PCR and BLAST of RNA-Seq datasets. RESULTS: We observed in the rat forebrain progressive decline of total Fmr1 mRNA from E11 to P112 albeit an elevation on P3; and exon-14 skipping in E17-E20 with downregulation of the resulting mRNA. We tested if the reduced detection of messages without exon 14 could be explained by nonsense-mediated mRNA decay (NMD) vulnerability, but knocking down UPF1, a major component of this pathway, did not increase their quantities. Conversely, it significantly decreased FMR1 mRNA having exon 13 joined with either exon 14 or exon 15 site A. CONCLUSIONS: The forebrain in the third embryonic week of the rat development is a period with significant skipping of Fmr1 exon 14. This alternative splicing event chronologically precedes a reduction of total Fmr1 mRNA, suggesting that it may be part of combinatorial mechanisms downregulating the gene's expression in the late embryonic period. The decay of FMR1 mRNA without exon 14 should be mediated by a pathway different from NMD. Finally, we provide evidence of FMR1 mRNA stabilization by UPF1, likely depending on FMRP.

Hepatic Venous Outflow Obstruction in Adult Deceased Donor Liver Transplantation: Classic Piggyback Implantation Versus a Modified Technique that Widens the Ostium of the Recipient's Left and Middle Hepatic Veins.

BACKGROUND: The classic piggyback technique uses the union of the 3 hepatic veins to perform the cavo-caval anastomosis. However, due to the lateral localization of the right hepatic vein, the partial clamping of the vena cava in this technique significantly reduces the venous return to the right atrium. To avoid this, we adopted in 2015 a modified piggyback technique, in which we use the common trunk of the middle and left hepatic veins and also perform a lateral incision toward the right in the anterior wall of the vena cava in order to widen the final ostium of the cavo-caval anastomosis. The aim of the study was to analyze the incidence of hepatic venous outflow obstruction between those 2 techniques. METHODS: Retrospective study of liver transplant recipients undergoing venography for suspected hepatic venous outflow obstruction from January 2009 to June 2021. Patients undergoing transplantation with living donors or split grafts and pediatric cases were excluded from the study. RESULTS: From January 2009 to December 2014 and from January 2015 to June 2021, 587 (group 1) and 730 (group 2) deceased-donor liver transplants were performed with the classic and the modified piggyback techniques, respectively. The incidence of cases with suspected hepatic venous outflow obstruction in groups 1 and 2 were 1.87% (n = 11) and 0.95% (n = 7), respectively (P = 0,15). The number of confirmed patients with outflow blockage that required endovascular treatment during venography in groups 1 and 2 were 4 (0.68%) and 5 (0.68%), respectively (P = 0,31). CONCLUSIONS: This modified piggyback technique did not increase the incidence of hepatic venous outflow obstruction at our service.

Prognostic Factors Evaluation for Liver Transplant Mismatching: A New Way of Selecting and Allocating Organs.

BACKGROUND: Liver transplant (LT) is the standard therapy for end-stage liver disease. Advances in surgical techniques and immunosuppression protocols improved the results of LT by increasing long-term survival. Nevertheless, an adequate match between the donor and recipient is paramount for avoiding futile liver transplants. We aimed to identify the prognostic factors in donor-recipient LT matching. METHODS: Retrospective analysis of adult LT was conducted from January 2006 to December 2018, which included the following transplant modalities: deceased donor LT (DDLT), living donor LT (LDLT), combined liver-kidney transplant (CLKT), and domino LT (DLT). RESULTS: Among 1101 patients who underwent LT, 958 patients underwent DDLT, 92 patients underwent LDLT, 45 patients underwent CLKT, and 6 patients underwent DLT. The overall survival (OS) in 1, 5, and 10 years were 89%, 83%, and 82%, respectively. For DDLT, OS in 1, 5, and 10 years were 91%, 84%, and 82%, respectively. For LDLT, OS in 1, 5, and 10 years were 89%, 72%, and 69%, respectively. For CKLT, OS in 1, 5, and 10 years were 90%, 71%, and 71%, respectively. None of the DLT patients died. For DDLT, the factors that affected OS were the presence of fulminant liver failure (odds ratio [OR], 2.23; 95% CI, 1.18-4.18; P = .001), hemodialysis before LT (OR, 2.12; 95% CI, 1.27-3.5; P = .004), retransplant (OR, 4.74; 95% CI, 2.75-8.17; P = .000), and recipient age >60 years (OR, 1.86; 95% CI, 1.27-2.73; P = .001). For hospitalization before LT (due to an acute-on-chronic liver failure), the OR was 2.10 (95% CI, 1.29-3.42; P = .003). Donor intensive care unit time >7 days (OR, 1.46; 95% CI, 1.04-2.06; P = .02) was also associated with overall mortality. CONCLUSIONS: We identified prognostic factors in donor-recipient LT matching. Furthermore, we demonstrated that an adequate organ allocation with donor-recipient selection might increase graft survival and reduce waiting list mortality.

Relationship of Anatomic Variations and Arterial Reconstruction of the Hepatic Artery: Prevalence and Effect on Orthotopic Liver Transplantation.

BACKGROUND: Identifying anatomic variations of the hepatic artery is essential in liver transplantation. The artery supply is crucial for the procedure's success, and, in some cases of anatomic variations, they need reconstruction. Hepatic artery thrombosis is a severe vascular complication. This study evaluated the prevalence of anatomic variations and correlated arterial reconstructions with hepatic artery thrombosis. METHODS: We performed a retrospective analysis of medical records, adult patients undergoing liver transplant, donor's arterial anatomy, arterial reconstructions, and thrombosis after transplant from January 2019 to December 2020. RESULTS: Among 226 cases, 71% had normal anatomy. All these patients met Michel's classification subtypes, of which 161 (71%) were class I, which is the most common. The second most common variation was class II, with 25 donors (11%), followed by class III, with 17 donors (7.5%). Anatomic artery variations were a risk factor for hepatic artery thrombosis development (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.1-22.5; P = .002). In the same way, the artery reconstruction was associated with hepatic artery thrombosis arising with postoperative time (OR, 18.0; 95% CI, 4.9-57.5; P < .001). Global hepatic artery thrombosis occurred in 11 cases (4.87%). CONCLUSION: Anatomic hepatic artery variations are frequent and do not make liver transplant unfeasible. However, variations that require reconstruction may raise the risk of thrombosis.

Experimental Clinical Model of Liver Transplantation in Large White Pigs Without Venovenous Bypass: Pre-, Intra-, and Maintenance Care.

BACKGROUND: Liver transplantation in an animal model is challenging due to hemodynamics and intraoperative anesthetic care. Several models are described in the literature employing different techniques such as venovenous bypass or aortic cross-clamping to maintain hemodynamic stability, although few groups keep the animal alive in the postoperative period. This study aims to evaluate a liver transplantation clinical model in pigs without venovenous bypass or aortic cross-clamping. METHODS: Male pigs weighing 20 to 35 kg underwent liver transplantation surgery without using venovenous bypass or aorta cross-clamping. Protocols were approved by the Animal Care and Use Committee of the University of São Paulo, Brazil. RESULTS: Ten LTs were performed. Cold ischemia and warm ischemia were 119 ± 33.28 minutes and 26 ± 9.6 minutes, respectively. Hemodynamic changes were significantly higher after the postrevasculazation phase: heart rate (P < .001), medium arterial pressure (P < .001), and cardiac output (P = .03). Hypotension was treated with intravenous fluids and, in some cases, with vasoactive drugs especially during the post-reperfusion period. No animals died during the procedure and almost survival until the first postoperative day. Serum aspartate aminotransferase and lactate increased their values in the post-reperfusion phase. CONCLUSIONS: Practice-based on laboratory animals improves surgical skills and the development of experimental models aimed at new advances in this field. Perfecting our technique on the swine model, we could move forward to create a small-for-size model, test new therapeutic strategies, and define the boundaries for safely performing an enlarged liver resection or a partial liver graft transplant.

Small-for-Size Syndrome: Systemic Review in a Porcine Experimental Model.

BACKGROUND: The small-for-size syndrome (SFSS) is characterized by prolonged hyperbilirubinemia, coagulopathy, and/or encephalopathy caused by a small liver graft that cannot sustain the metabolic demands of the recipient after a partial liver transplant (PLT). Models of PLT in pigs are excellent for studying this syndrome. This review aimed to identify the different porcine models of SFSS in the literature and compare their technical aspects and therapeutics methods focused on portal inflow modulation (PIM). METHODS: We performed a systematic review of the porcine experimental model and SFSS. The MEDLINE-PubMed, EMBASE, Cochrane Library, LILACS, and SciELO databases were electronically searched and updated until June 20, 2021. The MeSH terms used were ''ORGAN SIZE'' AND ''LIVER TRANSPLANTATION". RESULTS: Thirteen SFSS porcine models were reported. Four were performed with portocaval shunt to PIM and 3 with mesocaval shunt to PIM. A few studies focused on clinical therapeutics to PIM; a study described somatostatin infusion to avoid SFSS. Initially, studies on PIM showed its potentially beneficial effects without mentioning the minimum portal flow that permits liver regeneration. However, an excessive portal diversion could be detrimental to this process. CONCLUSIONS: The use of porcine models on SFSS resulted in a better understanding of its pathophysiology and led to the establishment of various types of portal modulation, surgical techniques with different complexities, and pharmaceutical strategies such as somatostatin, making clear that without reducing the portal vein pressure the outcomes are poor. With the improvement of these techniques, SFSS can be avoided.

Custo efetividade do uso da terlipressina no tratamento da síndrome hepatorrenal / Cost effectiveness of using terlipressin to treat hepatorenal syndrome

ABSTRACT Background Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. Objective: To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. Methods: Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. Results: After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. Conclusion: A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

RESUMO Contexto: A Síndrome Hepatorrenal (SHR) é a forma mais grave de lesão renal aguda em pacientes com cirrose avançada, estando diretamente associada a alta taxa de mortalidade. Normalmente é diagnosticada seguindo critérios definidos pela International Ascites Club (IAC). Atualmente, as terapias farmacológicas mais indicadas no tratamento da SHR são a combinação de vasoconstritores esplâncnicos (terlipressina ou norepinefrina) associados à albumina. Com o aumento progressivo dos gastos em saúde, torna-se relevante realizar uma análise de custo-efetividade do tratamento farmacológico em pacientes com diagnóstico de SHR. Objetivo: Realizar avaliação de custo-efetividade do uso da terlipressina associada à albumina no tratamento da SHR em pacientes com cirrose. Métodos: Avaliação econômica de custo-efetividade, com base em dados secundários de estudos publicados com resultado da eficácia da terapia com terlipressina, em comparação com norepinefrina combinada com albumina ou apenas albumina. A análise de custo-efetividade foi calculada usando a razão de custo-efetividade incremental (RCEI) e uma análise de sensibilidade foi desenvolvida variando os valores das terapias e probabilidades. O real foi a moeda utilizada na análise. Resultados: Após a seleção, elegibilidade e avaliação da qualidade das publicações, os resultados demonstraram que a administração da associação de terlipressina ou norepinefrina com albumina em pacientes diagnosticados com SHR tipo 1 possui eficácia comprovada. Os custos do tratamento com a terapia combinada de terlipressina com albumina foram de USD $1,644.06, administração de somente albumina USD $912.02 e norepinefrina mais albumina USD $2,310.78. Considerando as terapias combinadas com efetividade terapêutica comprovada, isto é, terlipressina e norepinefrina associada a albumina, o custo incremental foi de USD $666.73 e efetividade de 0,570 para o grupo da terlipressina associada a albumina e de 0,200 para o grupo da norepinefrina associada a albumina. A efetividade incremental foi de 0,370 e o valor da RCEI foi de USD $1,801.97. Assim, os fatores de incremento do custo por terapia e razão de custo-efetividade incremental definem que a terapia combinada de terlipressina mais albumina é custo efetiva quando comparada a administração de somente albumina ou norepinefrina no cenário do sistema único de saúde. Conclusão: O estudo demonstrou por meio de uma análise de custo-efetividade que a terlipressina associada à albumina quando administrada concomitantemente a pacientes com diagnóstico de SHR tipo 1 é custo-efetiva quando comparada à albumina sozinha e com norepinefrina associada à albumina administrada em um ambiente controlado.

Incidence of Donor Hepatic Artery Thrombosis in Liver Grafts Recognized During Organ Procurement and Backtable: A Rare but Treacherous Pitfall In Liver Transplantation.

INTRODUCTION: Donor hepatic artery thrombosis (dHAT) identified during liver procurement and backtable is a rare and little-reported event that can make liver transplants unfeasible. METHODS: This is a retrospective study of dHAT identified during liver grafts procurements or backtable procedures. All grafts were recovered from brain-dead donors. The demographic characteristics of the donors and the incidence of dHAT were analyzed. The data were also compared to a cohort of donors without dHAT. RESULTS: There was a total of 486 donors during the study period. The incidence of dHAT was 1.85% (n = 9). The diagnosis of dHAT was made during procurement in 5 cases (55.5%) and during the backtable in 4 (44.4%). Most donors were female (n = 5), with an average BMI of 28.14 ± 6.9 kg/m2, hypertensive (n = 5), and with stroke as cause of brain death (n = 8). The most prevalent site of dHAT was a left hepatic artery originating from the left gastric artery (n = 4). Of the 9 cases reported, 2 livers were used for transplantation, and 7 were discarded. Comparing those cases to a cohort of 260 donors without dHAT, we found a higher incidence of anatomic variations in the hepatic artery (P = .01) and of stroke as cause of brain death (P = .05). CONCLUSION: The occurrence of dHAT before liver procurement is a rare event, however it may become a treacherous pitfall if the diagnosis is late. Grafts with anatomic variations recovered from women with brain death due to stroke and with past history of hypertension seem to be at a higher risk of presenting dHAT.