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2.
PLoS One ; 15(5): e0231044, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357147

RESUMO

BACKGROUND/AIMS: The aim of our study was to evaluate the diagnostic accuracy of B-Mode ultrasound and Hepatorenal Index (HRI) by high-end devices for the detection and classification of hepatic steatosis in patients with various causes of chronic liver disease (CLD). METHODS: We retrospectively enrolled patients with CLD who underwent liver biopsy and baseline ultrasound between March 2016 and May 2019. Sonographic graduation of steatosis (0°-III°) using B-Mode criteria and HRI were correlated with the histological graduation (S0 (<5% fat), S1 (≥5-33%), S2 (>33-66%) and S3 (>66%). Interobserver agreement was calculated. RESULTS: 157 patients were evaluated. B-Mode ultrasound had a sensitivity of 75.6% and a specificity of 76.0% to differentiate between steatosis and no steatosis (AUROC 0.758). Using B-Mode criteria for advanced steatosis (≥II°), specificity for presence of histological steatosis was ≥98.7%. For detection of advanced steatosis (≥S2), sensitivity of B-mode criteria was 90.9%. In a subgroup of patients with advanced liver fibrosis, sensitivity of B-mode criteria was 95.0% for detection of advanced steatosis (S≥2). A HRI cut-off-value of 1.46 differentiates between patients with steatosis and patients without steatosis with a sensitivity of 42.7% and a specificity of 90.7% (AUROC 0.680). Interobserver agreement of both B-Mode and HRI was good to excellent. CONCLUSION: B-Mode ultrasound using high-end devices is an excellent method to detect advanced steatosis in patients with various CLD. For diagnosis of mild steatosis, modern ultrasound devices may have higher sensitivity but at the expense of specificity. Stage of fibrosis and etiology of CLD seem not to impact on diagnostic accuracy. The additional calculation of HRI seems to have no additional benefit with regard to detect or grade hepatic steatosis in our study population.


Assuntos
Doença Hepática Terminal/complicações , Fígado Gorduroso/diagnóstico , Rim/patologia , Fígado/patologia , Ultrassonografia/métodos , Doença Hepática Terminal/diagnóstico por imagem , Doença Hepática Terminal/patologia , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/etiologia , Feminino , Humanos , Rim/diagnóstico por imagem , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
3.
Transplantation ; 104(6): e164-e173, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32150036

RESUMO

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) are waitlisted at older ages than individuals with other liver diseases, but the effect of age on liver transplantation (LT) outcomes in this population and whether it differs from other etiologies is not known. We aimed to evaluate the impact of age on LT outcomes in NASH. METHODS: The United Network for Organ Sharing database was used to identify adults with NASH, hepatitis C virus (HCV) infection, and alcohol-related liver disease (ALD) listed for LT during 2004-2017. Patients were split into age groups (18-49, 50-54, 55-59, 60-64, 65-69, ≥70), and their outcomes were compared. RESULTS: From 2004 to 2017, 14 197 adults with NASH were waitlisted, and the proportion ≥65 increased from 15.8% to 28.9%. NASH patients ages 65-69 had an increased risk of waitlist and posttransplant mortality compared to younger groups, whereas the outcomes in ages 60-64 and 55-59 were similar. The outcomes of individuals with NASH were similar to patients of the same age group with ALD or HCV. Functional status and dialysis were predictors of posttransplant mortality in individuals ≥65 with NASH, and cardiovascular disease was the leading cause of death. CONCLUSIONS: Older NASH patients (≥65) have an increased risk of waitlist and posttransplant mortality compared to younger individuals, although outcomes were similar to patients with ALD or HCV of corresponding age. These individuals should be carefully evaluated prior to LT, considering their functional status, renal function, and cardiovascular risk. Further studies are needed to optimize outcomes in this growing population of transplant candidates.


Assuntos
Doença Hepática Terminal/cirurgia , Fígado Gorduroso Alcoólico/cirurgia , Hepatite C/cirurgia , Transplante de Fígado/estatística & dados numéricos , Hepatopatia Gordurosa não Alcoólica/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Causas de Morte , Progressão da Doença , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Fígado Gorduroso Alcoólico/mortalidade , Fígado Gorduroso Alcoólico/patologia , Feminino , Hepatite C/mortalidade , Hepatite C/patologia , Humanos , Transplante de Fígado/normas , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/patologia , Seleção de Pacientes , Período Pós-Operatório , Estados Unidos/epidemiologia , Listas de Espera/mortalidade , Adulto Jovem
4.
Sci Rep ; 10(1): 2771, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066758

RESUMO

The presence of advanced fibrosis is an important measure of the severity of chronic liver disease. Prior works that have examined the gut microbiome as a novel biomarker for advanced fibrosis have only examined patients with nonalcoholic fatty liver disease. Therefore, our goal was to examine the gut microbiome across varying etiologies of liver disease to create a predictive model for liver fibrosis based upon a microbial signature. Stool samples were obtained from patients with chronic liver disease (n = 50) undergoing FibroScan (ultrasound elastography) at the VA Greater Los Angeles Healthcare System. Healthy control patients (n = 25) were also recruited as a reference population. Fecal samples underwent 16S ribosomal RNA sequencing. Using differentially abundant microbes, a random forest classifier model was created to distinguish advanced fibrosis from mild/moderate fibrosis. The findings were then validated in a separate cohort of chronic liver disease patients (n = 37). Etiologies for liver disease included non-alcoholic liver disease (58.0%), hepatitis C (26.0%), hepatitis B (10.0%), and alcohol (6.0%). Microbiome composition was distinct in liver patients with advanced fibrosis compared to those with minimal fibrosis and healthy controls (p = 0.003). In multivariate negative binomial modeling, 26 bacterial taxa were differentially abundant in patients with advanced fibrosis as compared to those with minimal/moderate fibrosis (q-value < 0.05). A random forests classifier based on these taxa had an AUROC of 0.90 to predict advanced fibrosis. Prevotella copri, which was enriched in patients with advanced fibrosis, was the most strongly predictive microbe in the classifier. The classifier had an AUROC of 0.82 for advanced fibrosis in the validation cohort and Prevotella copri remained the strongest predictive microbe for advanced fibrosis. There is a distinct microbial signature for patients with advanced fibrosis independent of liver disease etiology and other comorbidities. These results suggest that microbial profiles can be used as a non-invasive marker for advanced fibrosis and support the hypothesis that microbes and their metabolites contribute to hepatic fibrosis.


Assuntos
Doença Hepática Terminal/genética , Microbioma Gastrointestinal/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Doença Hepática Terminal/complicações , Doença Hepática Terminal/microbiologia , Doença Hepática Terminal/patologia , Fezes/microbiologia , Feminino , Humanos , Fígado/microbiologia , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/microbiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Prevotella/isolamento & purificação , Prevotella/patogenicidade , Índice de Gravidade de Doença
5.
Transplantation ; 104(6): 1187-1192, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31577674

RESUMO

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor with a high mortality rate. HEHE is now a formally recognized indication for exception point priority in the United States under the new National Liver Review Board. The role of liver transplantation (LT) and exception point waitlist priority in the United States for patients with HEHE remains understudied. METHODS: This was a retrospective cohort study using the United Network for Organ Sharing transplant database. From February 27, 2002 to January 31, 2018, 131 adults waitlisted for LT with HEHE were identified by free-text entry. RESULTS: Exception point applications were submitted for 91.6% (120/131) of patients. All patients with fully reviewed applications received exception points at least once during waitlisting, and 85% (103/120) upon first submission. Among the 88 patients transplanted, median model for end-stage liver disease score at LT was 7 ((interquartile range [IQR]: 6-11) and waiting time 78.5 days (IQR: 29.5-237.5). Unadjusted post-LT survival of HEHE recipients at 1-, 3-, and 5-years from LT was 88.6%, 78.9%, and 77.2%. Unadjusted post-LT patient and graft survival of HEHE patients was not different from patients with hepatocellular carcinoma within Milan receiving exception point priority (P = 0.08). An increased rate of graft failure due to hepatic artery thrombosis ≤14 days from initial LT was observed in HEHE versus non-HEHE patients (4.6% versus 0.5%). CONCLUSIONS: The majority of HEHE recipients receive exception points at a universal approval rate allowing prompt access to deceased donor LT.


Assuntos
Carcinoma Hepatocelular/cirurgia , Doença Hepática Terminal/cirurgia , Hemangioendotelioma Epitelioide/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/estatística & dados numéricos , Adulto , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Bases de Dados Factuais/estatística & dados numéricos , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/mortalidade , Hemangioendotelioma Epitelioide/patologia , Artéria Hepática/patologia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Trombose/epidemiologia , Trombose/etiologia , Trombose/patologia , Resultado do Tratamento , Estados Unidos , Listas de Espera/mortalidade
6.
Transplantation ; 104(1): 97-103, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31205265

RESUMO

BACKGROUND: Time spent on the waiting list before liver transplantation (LT) provides an opportunity to optimize recipient fitness through prehabilitation, potentially reducing the physiological impact of major surgery. We assessed the feasibility and effectiveness of a 6-week exercise program in patients with cirrhotic liver disease awaiting LT. METHODS: This single-center, prospective cohort, feasibility study, enrolled patients awaiting LT to a 6-week period of thrice weekly, supervised exercise on a static bike. Cardiopulmonary exercise testing (CPET) was used to objectively assess cardiopulmonary fitness at baseline and after 6 weeks of exercise. A follow-up CPET was performed at 12 weeks. CPET-derived measures were used to guide prescription of the training program. A nonrandomized control cohort of LT patients were selected to match the exercise group based on specific demographic data. Allocation to study arms was primarily based on the distance participants lived from the hospital where training occurred. Both groups received structured nutritional advice. RESULTS: The exercise program was feasible, with 9 of 16 (56%) patients completing the full program of 6 weeks. Peak oxygen consumption (VO2peak) in the exercise group rose from a mean (SD) of 16.2 (±3.4) mL/kg/min at baseline to 18.5 (±4.6) mL/kg/min at week 6 (P = 0.02). In the control group, VO2peak decreased from a mean (SD) of 19.0 (±6.1) mL/kg/min to 17.1 (±6.0) at week 6 (P = 0.03). CONCLUSIONS: We have demonstrated that it is feasible to engage patients awaiting LT in an intensive aerobic exercise program with a signal of improvement in fitness being detected.


Assuntos
Doença Hepática Terminal/reabilitação , Terapia por Exercício/métodos , Cirrose Hepática/reabilitação , Transplante de Fígado , Ambulatório Hospitalar/organização & administração , Doença Hepática Terminal/patologia , Doença Hepática Terminal/cirurgia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Aptidão Física , Período Pré-Operatório , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Listas de Espera
7.
Transplantation ; 104(7): 1413-1418, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31644488

RESUMO

BACKGROUND: The vast majority of patients with cirrhosis have low Model for End-Stage Liver Disease-Sodium (MELD-Na) scores; however, the ability for the MELD-Na score to predict patient outcomes at low scores is unclear. METHODS: Adult patients in a multicenter, Chicago-wide database of medical records with International Classification of Disease, Ninth Edition codes of cirrhosis and without a history of hepatocellular carcinoma were included. Records were linked with the state death registry, and death certificates were manually reviewed. Deaths were classified as "liver-related," "non-liver-related," and "non-descript" as adjudicated by a panel comprised of a transplant surgeon, a hepatologist, and an internist. A sensitivity analysis was performed where patients with hepatocellular carcinoma were included. RESULTS: Among 7922 identified patients, 3999 patients had MELD-Na scores that were never higher than 15. In total, 2137 (27%) patients died during the study period with higher mortality rates for the patients in the high MELD-Na group (19.4 (41.6%) versus 4.1 (12.6%) per 100 person-y, P < 0.001). The high MELD-Na group died of a liver-related cause in 1142 out of 1632 (70%) as compared to 240 out of 505 (47.5%) deaths in the low MELD-Na group. There was no difference in the distribution of subcategory of liver-related death between low and high MELD-Na groups. Among subclassification of liver-related deaths, the most common cause of death was "Infectious" in both groups. CONCLUSIONS: Despite persistently low MELD-Na scores, patients with cirrhosis still experience high rates of liver-related mortality.


Assuntos
Doença Hepática Terminal/mortalidade , Cirrose Hepática/mortalidade , Índice de Gravidade de Doença , Sódio/sangue , Listas de Espera/mortalidade , Adulto , Idoso , Causas de Morte , Chicago/epidemiologia , Atestado de Óbito , Progressão da Doença , Doença Hepática Terminal/sangue , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/patologia , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Transplante de Fígado/normas , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Medição de Risco/estatística & dados numéricos , Fatores de Tempo
8.
Nutrients ; 11(12)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817398

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is expected to become the leading cause of end-stage liver disease worldwide over the next few decades. In fact, NAFLD encompasses different clinical scenarios, from the simple accumulation of fat (steatosis) to steatohepatitis (NASH), NASH-cirrhosis, and cirrhosis complications. In this context, it is fundamental to pursue strategies aimed at both preventing the disease and reducing the progression of liver fibrosis once liver damage is already initiated. As of today, no pharmacological treatment has been approved for NAFLD/NASH, and the only recommended treatment of proven efficacy are life-style modifications, including diet and physical exercise pointing at weight loss of 5%-7%. Different dietetic approaches have been proposed in this setting, and in this review, we will discuss the evidence regarding the efficacy of the Mediterranean Diet as a treatment for NAFLD. In particular, we will report the effects on liver-related outcomes.


Assuntos
Dieta Mediterrânea , Hepatopatia Gordurosa não Alcoólica/terapia , Tecido Adiposo/patologia , Adiposidade , Doença Hepática Terminal/patologia , Medicina Baseada em Evidências , Exercício Físico , Humanos , Estilo de Vida , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Resultado do Tratamento , Perda de Peso
9.
Biomolecules ; 9(12)2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835520

RESUMO

In an era of improved survival due to modern antiretroviral therapy, liver disease has become a major cause of morbidity and mortality, resulting in death in 15-17% of human immunodeficiency virus (HIV)-infected patients. Alcohol enhances HIV-mediated liver damage and promotes the progression to advanced fibrosis and cirrhosis. However, the mechanisms behind these events are uncertain. Here, we hypothesize that ethanol metabolism potentiates accumulation of HIV in hepatocytes, causing oxidative stress and intensive apoptotic cell death. Engulfment of HIV-containing apoptotic hepatocytes by non-parenchymal cells (NPCs) triggers their activation and liver injury progression. This study was performed on primary human hepatocytes and Huh7.5-CYP cells infected with HIV-1ADA, and major findings were confirmed by pilot data obtained on ethanol-fed HIV-injected chimeric mice with humanized livers. We demonstrated that ethanol exposure potentiates HIV accumulation in hepatocytes by suppressing HIV degradation by lysosomes and proteasomes. This leads to increased oxidative stress and hepatocyte apoptosis. Exposure of HIV-infected apoptotic hepatocytes to NPCs activates the inflammasome in macrophages and pro-fibrotic genes in hepatic stellate cells. We conclude that while HIV and ethanol metabolism-triggered apoptosis clears up HIV-infected hepatocytes, continued generation of HIV-expressing apoptotic bodies may be detrimental for progression of liver inflammation and fibrosis due to constant activation of NPCs.


Assuntos
Doença Hepática Terminal , Etanol , Hepatócitos/efeitos dos fármacos , Acetaldeído/toxicidade , Animais , Apoptose , Linhagem Celular , Progressão da Doença , Doença Hepática Terminal/patologia , Doença Hepática Terminal/virologia , Etanol/metabolismo , Etanol/toxicidade , HIV/patogenicidade , Infecções por HIV/complicações , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/virologia , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Camundongos , Estresse Oxidativo
10.
Biomed Res Int ; 2019: 7284040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737675

RESUMO

Inflammatory markers have been studied in cancers and chronic states of inflammation. They are thought to correlate with tumor pathology through disruption of normal homeostasis. Markers such as neutrophil to lymphocyte ratio (NLR) among others have shown promise as prognostic tools in various cancers. In this study, we evaluate complete blood count based inflammatory markers in hepatocellular carcinoma (HCC) to predict overall and recurrence-free survival of patients after liver transplant. Between 2001 and 2017, all HCC indicated liver transplants were retrospectively reviewed. Inclusion criteria included presence of complete blood cell counts with differential within three months prior to transplantation. Exclusion criteria included retransplantation and inadequate posttransplant followup. A total of 160 patients with HCC were included in the study. Of those, 74.4% had hepatitis C virus as the underlying cause of HCC. Calculated Model for End stage Liver Disease (MELD) scores were statistically worse in patients with elevated NLR (≥5), derived NLR (≥3), and low lymphocyte to monocyte ratio (LMR) (<3.45), whereas elevated platelet to lymphocyte ratio (PLR) (≥150) did not correlate with MELD. Of the tumor characteristics, low LMR was associated with tumor presence and microvascular invasion on explant. Though overall survival trended towards better outcomes with low NLR and dNLR and high LMR, these did not reach statistical significance. High LMR also trended towards better recurrence-free survival without statistical significance. Low PLR was associated with statistically significant overall and recurrence-free survival. In conclusion, while prior studies in HCC have identified NLR as surrogate for tumor burden and survival, in this study we highlight that PLR is a good surrogate of mortality and recurrence-free survival in HCC transplant patients. Further, future study of PLR, NLR, and LMR in larger HCC populations before and after interventions may help clarify their clinical utility as a simple and noninvasive clinical tool as prognostic markers.


Assuntos
Carcinoma Hepatocelular/sangue , Inflamação/sangue , Neoplasias Hepáticas/sangue , Transplante de Fígado/efeitos adversos , Biomarcadores Tumorais/sangue , Contagem de Células Sanguíneas , Plaquetas/metabolismo , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Doença Hepática Terminal/sangue , Doença Hepática Terminal/patologia , Feminino , Hepacivirus/patogenicidade , Humanos , Inflamação/etiologia , Inflamação/patologia , Fígado/patologia , Neoplasias Hepáticas/patologia , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Neutrófilos/citologia , Contagem de Plaquetas
11.
Postepy Biochem ; 65(3): 193-201, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643166

RESUMO

Liver diseases that lead to its failure are one of the most frequent causes of death worldwide. Taking into account liver's complexity, there are no drug for acute or acute on chronic liver failure treatment. So far the only effective therapy is the liver transplantation. Unfortunately donor shortage is a main problem of this therapy. Due to this fact scientists have been looking for a new alternatives. The most promising are cell transplantation and bioartificial support systems. Without doubt hepatocytes are the best source of cells to use. But isolated human hepatocytes dedifferentiate very quickly and lose their functions ex vivo. Therefore, the new sources of cells, which could replace hepatocytes, are highly sought after. It is believed that, in order to help patients suffering from liver disease, the approach to solve this problem should be considered on different levels.


Assuntos
Doença Hepática Terminal/terapia , Hepatócitos/citologia , Hepatócitos/transplante , Fígado Artificial , Doença Hepática Terminal/patologia , Doença Hepática Terminal/fisiopatologia , Hepatócitos/patologia , Humanos
12.
Nat Med ; 25(10): 1560-1565, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591593

RESUMO

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 107, 108 or up to 109 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Doença Hepática Terminal/terapia , Cirrose Hepática/terapia , Macrófagos/transplante , Idoso , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Relação Dose-Resposta Imunológica , Doença Hepática Terminal/imunologia , Doença Hepática Terminal/patologia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Regeneração Hepática , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade
13.
Clin Transplant ; 33(11): e13721, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31556146

RESUMO

AIM/BACKGROUND: Domino liver transplantation (DLT) using liver allografts from patients with metabolic disorders enhances organ utilization. Short- and long-term course and outcome of these patients can impact the decision to offer this procedure to patients, especially those with diseases that can potentially be cured with liver transplant. We reviewed the outcomes of DLT from maple syrup urine disease (MSUD) patients in our large academic pediatric and adult transplant program. METHODS: All patients receiving DLT were analyzed retrospectively with a minimum of one-year follow-up period for patient and donor characteristics, early and late postoperative complications and patient and graft survival with their MSUD donors in terms of age, weight, MELD/PELD scores, cold ischemia time, postoperative leucine levels, and peak ALT (alanine aminotransferase) levels during the first 48 postoperative hours. RESULTS: Between 2006 and May 2019, 21 patients underwent domino liver transplantation with live donor allografts from MSUD patients. Four patients transplanted for different metabolic diseases are focus of a separate report. Seventeen patients with minimum one-year follow-up period are reported herein. The indications were primary sclerosing cholangitis (PSC, n = 4), congenital hepatic fibrosis (CHF, n = 2), alpha-1 antitrypsin deficiency (A-1 ATD, n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), cystic fibrosis (n = 1), primary biliary cirrhosis (PBC, n = 1), neonatal hepatitis (n = 1), embryonal sarcoma (n = 1), Caroli disease (n = 1), hepatocellular carcinoma (HCC, n = 1), and chronic rejection after liver transplantations for PSC (n = 1). All patients and grafts survived at median follow-up of 6.4 years (range 1.2-12.9 years). Median domino recipient age was 16.2 years (range 0.6-64.6 years) and median MSUD recipient age was 17.6 years (range 4.8-32.1 years). There were no vascular complications during the early postoperative period, one patient had portal vein thrombosis 3 years after DLT and a meso-Rex bypass was successfully performed. Small for size syndrome (SFSS) occurred in reduced left lobe DLT recipient and was managed successfully with conservative management. Biliary stricture developed in 2 patients and was resolved by stenting. Comparison between DLT and MSUD recipients' peak postoperative ALT results and PELD/MELD scores showed lower levels in DLT group (P-value <.05). CONCLUSIONS: Patient and graft survival in DLT from MSUD donors was excellent at short- and long-term follow-up. Metabolic functions have been normal in all recipients on a normal unrestricted protein diet. Ischemia preservation injury based on peak ALT was significantly decreased in DLT recipients. Domino transplantation from pediatric and adult recipients with selected metabolic diseases should be increasingly considered as an excellent option and alternative to deceased donor transplantation, thereby expanding the living donor pool. This, to date, is the largest world experience in DLT utilizing livers from patients with MSUD.


Assuntos
Doença Hepática Terminal/mortalidade , Rejeição de Enxerto/mortalidade , Transplante de Fígado/mortalidade , Doadores Vivos/provisão & distribução , Doença da Urina de Xarope de Bordo/fisiopatologia , Complicações Pós-Operatórias/mortalidade , Transplantados/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Doença Hepática Terminal/patologia , Doença Hepática Terminal/cirurgia , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
14.
Curr Mol Med ; 20(1): 60-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31530262

RESUMO

BACKGROUND: Sarcopenia is characterized by the loss of muscle mass and strength (muscle atrophy) because of aging or chronic diseases, such as chronic liver disease (CLD). Different mechanisms are involved in skeletal muscle atrophy, including decreased muscle fibre diameter and myosin heavy chain levels and increased ubiquitin-proteasome pathway activity, oxidative stress and myonuclear apoptosis. We recently found that all these mechanisms, except myonuclear apoptosis, which was not evaluated in the previous study, were involved in muscle atrophy associated with hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLD. OBJECTIVE: In the present study, we evaluated the involvement of myonuclear apoptosis in CLD-associated sarcopenia and the effect of N-acetyl cysteine (NAC) treatment on muscle strength and apoptosis, using a DDC-supplemented diet-fed mouse model. METHODS: Four-month-old male C57BL6 mice were fed with a standard or DDCsupplemented diet for six weeks in the absence or presence of NAC treatment. RESULTS: Our results showed that NAC attenuated the decrease in muscle fibre diameter and muscle strength associated with CLD-induced muscle wasting in gastrocnemius (GA) muscle of DDC-supplemented diet-fed mice. In addition, in GA muscle of the mice fed with DDC-supplemented diet-induced CLD showed increased myonuclear apoptosis compared with the GA muscle of the control diet-fed mice, as evidenced by increased apoptotic nuclei number, caspase-8 and caspase-9 expression, enzymatic activity of caspase-3 and BAX/BCL-2 ratio. NAC treatment inhibited all the mechanisms associated with myonuclear apoptosis in the GA muscle. CONCLUSION: To our knowledge, this is the first study which reports the redox regulation of muscle strength and myonuclear apoptosis in CLD-induced sarcopenia.


Assuntos
Acetilcisteína/farmacologia , Doença Hepática Terminal/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Sarcopenia/tratamento farmacológico , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Doença Hepática Terminal/induzido quimicamente , Doença Hepática Terminal/complicações , Doença Hepática Terminal/patologia , Humanos , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Estresse Oxidativo/efeitos dos fármacos , Piridinas/toxicidade , Sarcopenia/etiologia , Sarcopenia/metabolismo , Sarcopenia/patologia
15.
Cells ; 8(10)2019 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-31546729

RESUMO

Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects-expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.


Assuntos
Fígado/citologia , Fígado/fisiologia , Células-Tronco Mesenquimais/fisiologia , Tecido Adiposo/citologia , Adulto , Diferenciação Celular/fisiologia , Doença Hepática Terminal/patologia , Doença Hepática Terminal/fisiopatologia , Doença Hepática Terminal/terapia , Hepatócitos/fisiologia , Humanos , Imunomodulação/fisiologia , Transplante de Células-Tronco Mesenquimais
16.
Cell Transplant ; 28(12): 1490-1506, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31512503

RESUMO

Liver transplantation has been deemed the best choice for end-stage liver disease patients but immune rejection after surgery is still a serious problem. Patients have to take immunosuppressive drugs for a long time after liver transplantation, and this often leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to researchers because of their powerful immunomodulatory effects. In the past, a large number of in vitro and in vivo studies have demonstrated the great potential of MSCs for participation in posttransplant immunomodulation. In addition, MSCs also have properties that may potentially benefit patients undergoing liver transplantation. This article aims to provide an overview of the current understanding of the immunomodulation achieved by the application of MSCs in liver transplantation, to discuss the problems that may be encountered when using MSCs in clinical practice, and to describe some of the underlying capabilities of MSCs in liver transplantation. Cell-cell contact, soluble molecules, and exosomes have been suggested to be critical approaches to MSCs' immunoregulation in vitro; however, the exact mechanism, especially in vivo, is still unclear. In recent years, the clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to the clinical application of MSCs are decreasing, but large sample clinical trials involving MSCs are still needed to further study their clinical effects.


Assuntos
Imunomodulação , Transplante de Fígado , Células-Tronco Mesenquimais/imunologia , Doença Hepática Terminal/imunologia , Doença Hepática Terminal/patologia , Doença Hepática Terminal/cirurgia , Humanos , Transplante de Células-Tronco Mesenquimais
17.
Liver Transpl ; 25(11): 1611-1619, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31529607

RESUMO

Up to 50% of liver transplantation (LT) recipients with known or clandestine alcohol-use disorder (AUD) before surgery return to alcohol use after LT. However, only severe alcohol relapse, which varies in frequency from 11% to 26% of patients, has an impact on longterm survival and significantly decreases survival rates after 10 years. Therefore, it is crucial to identify patients with the highest risk of severe relapse in order to arrange specific, standardized monitoring by an addiction team before and after LT. The aims of this study were to describe the effects of combined management of AUD on the rate of severe alcohol relapse and to determine the risk factors before LT that predict severe relapse. Patients transplanted between January 2008 and December 2014 who had met with the LT team's addiction specialist were included in the study. Patients who exhibited alcohol-related relapse risk factors received specific addiction follow-up. A total of 235 patients were enrolled in the study. Most of them were men (79%), and the mean age at the time of the LT was 55.7 years. Severe relapse occurred in only 9% of the transplant recipients. Alcohol-related factors of severe relapse were a pretransplant abstinence of 6 months and family, legal, or professional consequences of alcohol consumption, whereas the nonalcohol-related factors were being single and being eligible for a disability pension. In conclusion, the integration of an addiction team in a LT center may be beneficial. The addiction specialist can identify patients at risk of severe relapse in the pretransplantation period and hence arrange for specific follow-up.


Assuntos
Abstinência de Álcool/estatística & dados numéricos , Alcoolismo/prevenção & controle , Transplante de Fígado , Equipe de Assistência ao Paciente/organização & administração , Prevenção Secundária/organização & administração , Medicina do Vício , Assistência ao Convalescente/métodos , Assistência ao Convalescente/organização & administração , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Alcoolismo/reabilitação , Estudos de Coortes , Progressão da Doença , Doença Hepática Terminal/patologia , Doença Hepática Terminal/cirurgia , Feminino , Humanos , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/cirurgia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Prevenção Secundária/métodos , Índice de Gravidade de Doença
19.
J Pharmacol Exp Ther ; 371(2): 231-241, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31406003

RESUMO

Previous studies show that cyclophilins contribute to many pathologic processes, and cyclophilin inhibitors demonstrate therapeutic activities in many experimental models. However, no drug with cyclophilin inhibition as the primary mode of action has advanced completely through clinical development to market. In this study, we present findings on the cyclophilin inhibitor, CRV431, that highlight its potential as a drug candidate for chronic liver diseases. CRV431 was found to potently inhibit all cyclophilin isoforms tested-A, B, D, and G. Inhibitory constant or IC50 values ranged from 1 to 7 nM, which was up to 13 times more potent than the parent compound, cyclosporine A (CsA), from which CRV431 was derived. Other CRV431 advantages over CsA as a nontransplant drug candidate were significantly diminished immunosuppressive activity, less drug transporter inhibition, and reduced cytotoxicity potential. Oral dosing to mice and rats led to good blood exposures and a 5- to 15-fold accumulation of CRV431 in liver compared with blood concentrations across a wide range of CRV431 dosing levels. Most importantly, CRV431 decreased liver fibrosis in a 6-week carbon tetrachloride model and in a mouse model of nonalcoholic steatohepatitis (NASH). Additionally, CRV431 administration during a late, oncogenic stage of the NASH disease model resulted in a 50% reduction in the number and size of liver tumors. These findings are consistent with CRV431 targeting fibrosis and cancer through multiple, cyclophilin-mediated mechanisms and support the development of CRV431 as a safe and effective drug candidate for liver diseases. SIGNIFICANCE STATEMENT: Cyclophilin inhibitors have demonstrated therapeutic activities in many disease models, but no drug candidates have yet advanced completely through development to market. In this study, CRV431 is shown to potently inhibit multiple cyclophilin isoforms, possess several optimized pharmacological properties, and decrease liver fibrosis and tumors in mouse models of chronic liver disease, which highlights its potential to be the first approved drug primarily targeting cyclophilin isomerases.


Assuntos
Ciclofilinas/antagonistas & inibidores , Ciclosporinas/uso terapêutico , Modelos Animais de Doenças , Doença Hepática Terminal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclosporinas/farmacologia , Relação Dose-Resposta a Droga , Doença Hepática Terminal/patologia , Feminino , Humanos , Células Jurkat , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Ratos , Ratos Sprague-Dawley , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia
20.
Liver Transpl ; 25(11): 1620-1633, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31469227

RESUMO

Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX), which can lead to progressive liver disease characterized by recurrent EPP crises and end-stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X-linked EPP. No patient had follow-up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX-lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX-lowering treatment with the intensity adjusted to achieve a target Erc-PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.


Assuntos
Doença Hepática Terminal/terapia , Rejeição de Enxerto/epidemiologia , Transplante de Fígado , Protoporfiria Eritropoética/patologia , Transplante de Células-Tronco , Listas de Espera/mortalidade , Adolescente , Adulto , Aloenxertos/patologia , Progressão da Doença , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Feminino , Rejeição de Enxerto/patologia , Humanos , Lactente , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Protoporfiria Eritropoética/mortalidade , Protoporfiria Eritropoética/terapia , Recidiva , Sistema de Registros/estatística & dados numéricos , Transplante Homólogo , Adulto Jovem
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