RESUMO
BACKGROUND AND AIMS: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology. APPROACH AND RESULTS: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response. CONCLUSION: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.
Assuntos
Doença Hepática Terminal/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Organoides/metabolismo , Adulto , Idoso , Biópsia , COVID-19/complicações , COVID-19/virologia , Diferenciação Celular/imunologia , Doença Hepática Terminal/imunologia , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fígado/citologia , Fígado/imunologia , Regeneração Hepática , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/virologia , Organoides/imunologia , SARS-CoV-2/imunologia , Regulação para Cima/imunologiaRESUMO
Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P < 0.001; odds ratio [OR], 4.16; P < 0.001). Portal vein thrombosis (PVT) similarly correlated with occult disease (OR, 1.97; P = 0.02). Explant tumor burden was equivalent between TIPS subgroups; accordingly, TIPS status was not independently associated with reduced DFS or OS. However, exceeding the Milan criteria was associated with reduced DFS (hazard ratio, 3.21; P = 0.001), and TIPS status in patients with a single suspected lesion (n = 316) independently correlated with explant tumor burdens beyond these criteria (OR, 13.47; P = 0.001). TIPS on pretransplant imaging are associated with occult HCC on explant pathology. Comparable occult disease findings in patients with PVT suggest that the mechanism may involve altered hepatic perfusion, obscuring imaging diagnosis. TIPS are not independently associated with reduced DFS or OS but are associated with exceeding the Milan criteria for patients with a single suspected lesion. The presence of TIPS may necessitate a higher index of suspicion for occult HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Derivação Portossistêmica Transjugular Intra-Hepática , Carcinoma Hepatocelular/cirurgia , Estudos de Casos e Controles , Humanos , Cirrose Hepática , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The 5-year incidence of posttransplant hepatocellular carcinoma (HCC) recurrence is 8%-20%. Several studies have evaluated pretransplant risk factors for HCC recurrence, but nearly all data have treated HCC as a homogeneous condition across all etiologies of liver disease despite differences in tumor biology and baseline incidence of HCC. We sought to evaluate the impact of etiology of liver disease, maximum pretransplant alpha-fetoprotein (AFP), and the interaction of the 2 factors on the risk of HCC recurrence. We performed a retrospective cohort study of HCC transplant recipients using United Network for Organ Sharing (UNOS) data from 2002 to 2016. A competing risks regression was performed to identify variables associated with HCC recurrence and an interaction term between etiology and maximum AFP category. Among 18,406 recipients, 1484 patients experienced HCC recurrence over 3.1 years of median follow-up time. There was a significant interaction between AFP category and etiology of liver disease (P < 0.001). Among patients with a maximum AFP <100 ng/mL, those with alcoholic liver disease had the lowest risk of recurrence. In contrast, in patients with a maximum AFP of 100-499, 500-1000, or >1000 ng/mL, those with alcoholic liver disease had the highest risk of HCC recurrence among all etiologies. In conclusion, risk of HCC recurrence differs by etiology of liver disease, and the significance of elevated pretransplant AFP varies by etiology. Patients with alcoholic liver disease and elevated maximum AFP are at a uniquely high risk of HCC recurrence. These findings have potential UNOS policy implications because the transplant selection process may ultimately benefit from etiology-specific criteria.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatopatias Alcoólicas/complicações , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Recidiva Local de Neoplasia/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/cirurgia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Seleção de Pacientes , Complicações Pós-Operatórias/etiologia , Período Pré-Operatório , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , alfa-Fetoproteínas/análiseRESUMO
BACKGROUND: Patients heterozygous for an abnormal α-1 antitrypsin (A1AT) mutation may have an increased risk of liver disease in the setting of a secondary contributing factor. METHODS: This single-center retrospective cohort study compared donor and recipient outcomes of A1AT heterozygous versus normal phenotype adult living-donor liver transplants (LDLTs). RESULTS: Between 2010 and 2016, 11 A1AT heterozygous donors and 10 recipients were compared to 57 normal donors and 41 recipients. There were no significant differences in sex, age, or race/ethnicity by A1AT phenotype. Heterozygous donors had significantly lower serum A1AT (median 100 mg/dL versus 131 mg/dL; P < 0.001). Median liver volume at 3 months post-LDLT was not different among donors or their recipients (1164 mm in heterozygous versus 1257 mm in normal [P = 0.449] for donors; 1563 mm versus 1606 mm [P = 0.387], respectively, for recipients). Recipient serum alkaline phosphatase at 1 month and 1 year post-LDLT was significantly higher in recipients of A1AT heterozygous grafts (160 U/L versus 99.5 U/L; P = 0.025 at 1 mo) but did not persist at 2 years. In addition, there was no association between A1AT level and liver volume at 3 months posttransplant in donors or recipients. CONCLUSIONS: Patients with a heterozygous A1AT mutation should be considered for living-liver donation.
Assuntos
Seleção do Doador , Heterozigoto , Transplante de Fígado , Doadores Vivos , Mutação , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adulto , Tomada de Decisão Clínica , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Fenótipo , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Deficiência de alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/diagnósticoRESUMO
Kidney paired exchange (KPE) constitutes 12% of all living donor kidney transplantations (LDKTs) in the United States. The success of KPE programs has prompted many in the liver transplant community to consider the possibility of liver paired exchange (LPE). Though the idea seems promising, the application has been limited to a handful of centers in Asia. In this article, we consider the indications, logistical issues, and ethics for establishing a LPE program in the United States with reference to the principles and advances developed from experience with KPE. Liver Transplantation 24 677-686 2018 AASLD.
Assuntos
Atenção à Saúde/organização & administração , Doação Dirigida de Tecido , Transplante de Rim/métodos , Transplante de Fígado/métodos , Doadores de Tecidos/provisão & distribuição , Atenção à Saúde/ética , Doação Dirigida de Tecido/ética , Seleção do Doador/organização & administração , Humanos , Consentimento Livre e Esclarecido , Transplante de Rim/ética , Transplante de Fígado/ética , Modelos Organizacionais , Avaliação de Programas e Projetos de Saúde , Doadores de Tecidos/ética , Estados Unidos , Fluxo de TrabalhoRESUMO
BACKGROUND: Patients with hepatocellular carcinoma (HCC) exceeding Milan criteria on explant pathology are at increased risk of recurrence and death. Discordance between contemporary magnetic resonance imaging (MRI) and explant pathology, and preoperative characteristics predictive of discordance are not well understood. METHODS: Patients who underwent orthotopic liver transplantation for HCC after preoperative MRI were identified in a prospectively collected institutional database (January 2003 to December 2013). Patients were dichotomized to "within" or "outside" Milan criteria by both imaging and explant pathologic evaluation. Binary logistic regression and Kaplan-Meier methodology were used to identify independent predictors of imaging/pathologic discordance and its impact on posttransplant survival. RESULTS: Of 318 patients with HCC meeting Milan criteria by MRI at the time of orthotopic liver transplantation, 248 (78.0%) remained within a pathological correlate of Milan criteria on explant examination. Understaging was associated with worse median recurrence-free survival (64.0 months vs 140.0 months, P = 0.002) and overall survival (96.0 months vs 143.0 months, P = 0.005), and did not vary between patients exceeding criteria due to tumor explant greater than 5 cm, more than 3 tumor foci, or a tumor greater than 3 cm in the setting of multifocality. Discordance was independently associated with an increasing serum alpha fetal protein level (odds ratio, 2.82; 95% confidence interval, 1.37-5.79; P = 0.005). CONCLUSIONS: Underestimating HCC burden before liver transplant remains frequent despite contemporary imaging technologies. Patients with an increasing alpha fetal protein before transplantation may benefit from more frequent testing or novel neoadjuvant therapies.
Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Transplante de Fígado , Imageamento por Ressonância Magnética , Estadiamento de Neoplasias/métodos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Tomada de Decisão Clínica , Bases de Dados Factuais , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga TumoralRESUMO
The ability to noninvasively diagnose acute cellular rejection (ACR) with high specificity and sensitivity would significantly advance personalized liver transplant recipient care and management of immunosuppression. We performed microRNA (miRNA) profiling in 318 serum samples from 69 liver transplant recipients enrolled in the Immune Tolerance Network immunosuppression withdrawal (ITN030ST) and Clinical Trials in Organ Transplantation (CTOT-03) studies. We quantified serum miRNA at clinically indicated and/or protocol biopsy events (n = 130). The trajectory of ACR diagnostic miRNAs during immunosuppression withdrawal were also evaluated in sera taken at predetermined intervals during immunosuppression minimization before and at clinically indicated liver biopsy (n = 119). Levels of 31 miRNAs were significantly associated with ACR diagnosis with two miRNAs differentiating ACR from non-ACR (area under the receiver operating characteristic curve = 90%, 95% confidence interval = 82%-96%) and predicted ACR events up to 40 days before biopsy-proven rejection. The most differentially expressed miRNAs were low or absent in the blood of healthy individuals but highly expressed in liver tissue, indicating an ectopic origin from the liver allograft. Pathway analyses of rejection-associated miRNAs and their target messenger RNAs (mRNAs) showed induction of proinflammatory and cell death-related pathways. Integration of differentially expressed serum miRNA with concordant liver biopsy mRNA demonstrates interaction between molecules with a known role in transplant rejection. CONCLUSION: Distinct miRNA levels profiled from sera at the time of clinical allograft dysfunction can be used to noninvasively diagnose ACR. Predictive trajectories of the same profile during supervised immunosuppression minimization diagnosed rejection up to 40 days prior to clinical expression. The rejection-associated miRNAs in sera appear to be ectopically expressed liver and specific immune cell miRNAs that are biologically related, and the consequences of immune-mediated damage to the allograft. (Hepatology 2017;65:269-280).
Assuntos
Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Transplante de Fígado , MicroRNAs/sangue , Expressão Ectópica do Gene , Feminino , Rejeição de Enxerto/genética , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Transcriptoma , Transplante HomólogoRESUMO
Vascularized composite allotransplantion requires careful planning and precise execution. The Director of the Hand Transplant Program must coordinate many personnel including nurses, anesthesiologists, transplant coordinators, surgeons, support staff, and hospital administrators. The operation is performed only after surgical rehearsal has reinforced the specialized role of each of these team members and the workflow of equipment and personnel has been optimized.
Assuntos
Mãos/cirurgia , Salas Cirúrgicas/organização & administração , Planejamento de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Alotransplante de Tecidos Compostos Vascularizados/normas , Humanos , Salas Cirúrgicas/normas , Planejamento de Assistência ao Paciente/normas , Equipe de Assistência ao Paciente/normasRESUMO
In this brief report, we summarize activity and trends in liver transplantation within the Penn Liver Transplant Program, including total program activity, recipient characteristics, waitlist time to transplant, graft and patient survival, rate of retransplantation, and multi-organ transplantation activity, as well as post-transplant hospital length of stay. RESULTS: Penn Transplant has performed 2478 total adult liver transplants to date, consisting of 2382 deceased-donor liver transplants and 96 living-donor liver transplants. Recipient race is approximately 70% white, 20% black, and 10% "other" races including Hispanic, Asian, and American Indian/Alaskan Native. Non-cholestatic cirrhosis is the leading indication for liver transplantation, accounting for more than half of all cases throughout the selected time interval. Most patients are not hospitalized at the time of transplantation, and there has been a reduction in the number of patients hospitalized in the intensive care unit at the time of transplant in the past five years. The median time to transplant is 13.2 months. Hazard ratios (HRs) for graft failure after one month, one year, and three years post-transplant were reported as: 0.54, 1.05, 1.01 (adult deceased donor) and 0.58, 0.57, 1.16 (adult living donor); HRs for patient survival were reported as: 0.44, 1.03, 1.04 (adult deceased donor) and 0.73, 0.74, 0.69 (adult living donor) for the same time increments. Penn averaged a 2.3% retransplantation rate and a total multi-organ transplant volume of 13. The mean length of hospital stay following transplantation was 8.83 days. CONCLUSION: Our program activity data mirrors trends that are seen in many of the established busy liver transplant centers in the United States. There is greater recognition that liver transplantation can be offered to a larger number of candidates who are diagnosed with progressive liver failure of primary cancer in the setting of liver cirrhosis, and there is an increase in donor organs from either extended criteria cadaveric donors or living donors. Despite more complex candidate populations and increased utilization of extended criteria donors, Penn's outcomes continue to be excellent. We postulate that the future depends on an increase in organ procurement organization activity, redesign of the national organ allocation system, and expansion of living donor activity.