RESUMO
The elderly demographic is the fastest-growing segment of the world's population and is projected to exceed 1.5 billion people by 2050. With multimorbidity, polypharmacy, susceptibility to drug-drug interactions, and frailty as distinct risk factors, elderly patients are especially vulnerable to developing potentially life-threatening safety events such as serious forms of drug-induced liver injury (DILI). It has been a longstanding shortcoming that elderly individuals are often a vulnerable population underrepresented in clinical trials. As such, an improved understanding of DILI in the elderly is a high-priority, unmet need. This challenge is underscored by recent documents put forward by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) that encourage data collection in the elderly and recommend improved practices that will facilitate a more inclusive approach. To establish what is already known about DILI in the elderly and pinpoint key gaps of knowledge in this arena, a working definition of "elderly" is required that accounts for both chronologic and biologic ages and varying states of frailty. In addition, it is critical to characterize the biological role of aging on liver function, as well as the different epidemiological factors such as polypharmacy and inappropriate prescribing that are common practices. While data may not show that elderly people are more susceptible to DILI, DILI due to specific drugs might be more common in this population. Improved characterization of DILI in the elderly may enhance diagnostic and prognostic capabilities and improve the way in which liver safety is monitored during clinical trials. This summary of the published literature provides a framework to understand and evaluate the risk of DILI in the elderly. Consensus statements and recommendations can help to optimize medical care and catalyze collaborations between academic clinicians, drug manufacturers, and regulatory scientists to enable the generation of high-quality research data relevant to the elderly population.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fragilidade , Humanos , Idoso , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fatores de Risco , Testes de Função HepáticaRESUMO
BACKGROUND: Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology. AIM: To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. METHODS: From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment. RESULTS: Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified. CONCLUSIONS: Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fígado Gorduroso , Humanos , Consenso , Fígado/patologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , BiópsiaRESUMO
Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Suscetibilidade a Doenças , Inibidores de Checkpoint Imunológico/efeitos adversos , Animais , Gerenciamento Clínico , Desenvolvimento de Medicamentos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Testes de Função Hepática , Neoplasias/complicações , Neoplasias/tratamento farmacológicoRESUMO
Drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH) are two of several types of drug-induced liver injury (DILI). They can be caused by various drugs and may present as acute, potentially lethal disorders or as chronic slowly progressive liver injury. Despite the fact that they are distinct disorders, the slow progressive forms of DIS and DISH are often confused with or misdiagnosed as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are much more common and, by definition, not caused by drugs. Currently the only way to identify DIS is via imaging studies or a liver biopsy, while DISH can be identified only through liver biopsy. In addition, diagnosis of either DIS or DISH requires an exhaustive clinical evaluation and comprehensive causality assessment to rule out other possible causes and determine the association with the suspected drug. Furthermore, it is difficult, using existing methods, to monitor the progression of DIS and DISH and to determine the underlying mechanism. Therefore, there is a great unmet need for non-invasive biomarkers that will be able to identify the development of DIS or DISH during drug development and to monitor for progression or regression of the disorder during treatment or following drug discontinuation. Recent developments in the fields of NAFLD and NASH have introduced several novel biomarkers that show promise for the diagnosis, monitoring, and severity assessment of these common diseases. Given the significant overlap in possible underlying mechanisms and histological pattern between NAFLD/NASH and DIS/DISH, these postulated NAFLD and NASH biomarkers may have a potential application to DIS and DISH. This article reviews the existing medical literature and other publically available information pertaining to novel serum biomarkers for NAFLD and NASH, and explores the concurrent identification of these biomarkers for DIS and DISH.
Assuntos
Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Fígado Gorduroso/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Progressão da Doença , Fígado Gorduroso/patologia , Humanos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
AIMS: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile. METHODS: Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. RESULTS: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. CONCLUSIONS: This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hipersensibilidade a Drogas/etiologia , Inibidores Enzimáticos/efeitos adversos , Imidazóis/efeitos adversos , Prostaglandina-E Sintases/antagonistas & inibidores , Administração Oral , Adulto , Área Sob a Curva , Celecoxib/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Hipersensibilidade a Drogas/patologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Suspensão de TratamentoRESUMO
Drug-induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3-5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high-risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high-risk drugs. CONCLUSION: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646-654).
Assuntos
Alanina Transaminase/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Preparações Farmacêuticas , Alanina Transaminase/metabolismo , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Feminino , Humanos , Testes de Função Hepática , Masculino , Medição de Risco , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Nonalcoholic steatohepatitis (NASH) is becoming a common cause of liver cirrhosis requiring liver transplantation (LT). Cardiovascular complications related to metabolic syndrome and NASH recurrence in the transplanted liver may affect the outcome of LT in these patients. We compared the outcomes of LT for NASH cirrhosis and alcoholic cirrhosis (ETOH) in a large transplant center. A retrospective chart review was performed for all patients who underwent LT for cryptogenic cirrhosis with the NASH phenotype (the NASH group) or ETOH (the ETOH group) at the University of Miami from January 1997 to January 2007. There was no significant difference in survival between the NASH and ETOH groups, despite a trend toward lower survival in the former (P = 0.1699). Sepsis was the leading cause of posttransplant death in both groups, and it was followed by cardiovascular causes in the NASH group (26% versus 7% in the ETOH group, P = 0.21) and malignancies in the ETOH group (29% versus 0% in the NASH group, P = 0.024). Recurrent steatohepatitis (33% versus 0%, P < 0.0001) and acute rejection (41% versus 23%, P < 0.023) were significantly more frequent in the NASH group than in the ETOH group. There was no difference in graft failure between the groups (24% in the NASH group versus 18% in the ETOH group, P = 0.3973). In conclusion, despite a numerical trend favoring the ETOH group, there were no statistically significant differences in posttransplant survival and cardiovascular mortality between the NASH and ETOH groups. Acute rejection and recurrent steatohepatitis were significantly more frequent in the NASH group but did not lead to higher rates of retransplantation.
Assuntos
Fígado Gorduroso/cirurgia , Cirrose Hepática Alcoólica/cirurgia , Cirrose Hepática/cirurgia , Transplante de Fígado , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Causas de Morte , Fígado Gorduroso/complicações , Fígado Gorduroso/mortalidade , Feminino , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/etiologia , Cirrose Hepática/mortalidade , Cirrose Hepática Alcoólica/mortalidade , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sepse/etiologia , Sepse/mortalidade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Eosinophilic cholangiopathy is a rare cholestatic disorder of unknown etiology. Simultaneous histologic documentation of eosinophilic involvement of the bile ducts and gastrointestinal tract has been reported previously in only a few well-documented cases. We report a 52-year-old man with a history of idiopathic hypereosinophilic syndrome who presented with acute diarrhea and cholestatic hepatitis. Colonoscopy revealed colitis, and a biopsy showed eosinophilic infiltrates in the colonic mucosa. Liver biopsy showed dense eosinophilic inflammation in the portal areas with bile duct damage. This case demonstrates the entity of hepatic involvement in idiopathic hypereosinophilic syndrome and the difficulties related to diagnosis and treatment.
Assuntos
Colestase Intra-Hepática/diagnóstico , Colite/diagnóstico , Síndrome Hipereosinofílica/diagnóstico , Anti-Inflamatórios/uso terapêutico , Ductos Biliares Intra-Hepáticos/patologia , Colestase Intra-Hepática/tratamento farmacológico , Colite/tratamento farmacológico , Humanos , Síndrome Hipereosinofílica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêuticoRESUMO
BACKGROUND: The outcome of liver transplantation (LT) in patients infected with human immunodeficiency virus (HIV) has been a matter of controversy. METHODS: A retrospective cohort study was performed to assess the impact of HIV on LT survival by using United Network for Organ Sharing registry Standard Transplant Analysis and Research files. RESULTS: A total of 138 HIV(+) and 30,520 HIV(-) patients who were > or =18 years old and underwent LT during the highly active antiretroviral therapy era (starting January 1, 1997) in the United States were included. Among all HIV(+) patients, the estimated 2-year survival probability was lower (70%) than among non-HIV patients (81%). This excess risk appeared entirely among those with coinfections, that is, HIV with hepatitis B virus or hepatitis C virus (HCV), as none of the 24 HIV-infected patients who did not have hepatitis B virus or HCV died during an average of 1.2 years of follow-up per person. Among HCV(+) patients, those with HIV coinfection had significantly lower survival rates than patients without HIV (P=0.006). Controlling for age, coinfection, Model for End-Stage Liver Disease scores, and other potential confounders in a proportional hazards regression analysis, HIV(+) patients had a hazard ratio of 1.41 (P=0.14, 95% confidence interval: 0.90-2.22) for mortality after LT. CONCLUSION: HIV(+) patients without HCV coinfection seemed to have good prognosis, whereas patients who had HIV/HCV coinfection had poor outcomes, which were significantly worse than that seen in those with HCV alone.
Assuntos
Síndrome da Imunodeficiência Adquirida/virologia , Bancos de Espécimes Biológicos/estatística & dados numéricos , HIV/fisiologia , Transplante de Fígado , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fatores de Risco , Taxa de SobrevidaRESUMO
Spontaneous resolution of chronic hepatitis C virus (HCV) infection is exceedingly rare and poorly understood. As HCV and human immunodeficiency virus (HIV) have shared routes of transmission, HCV coinfection is estimated to affect 15%-30% of the HIV-positive population. We report 2 patients with HCV-HIV coinfection who underwent orthotopic liver transplantation at our center and had spontaneous clearance of their chronic HCV infection after transplantation without any anti-HCV treatment. Both patients showed no evidence of HCV recurrence for more than 3 years despite long-term immunosuppressant therapy. Spontaneous clearance of chronic HCV infection can occur in HIV-HCV-coinfected patients after liver transplantation. The mechanism of this phenomenon remains unclear.
Assuntos
Infecções por HIV/complicações , HIV/isolamento & purificação , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Transplante de Fígado , Adulto , Seguimentos , HIV/genética , Infecções por HIV/virologia , Hepacivirus/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/cirurgia , Hepatite C Crônica/virologia , Humanos , Falência Hepática/etiologia , Falência Hepática/cirurgia , Masculino , Reação em Cadeia da Polimerase , RNA Viral/análise , Recidiva , Remissão EspontâneaRESUMO
BACKGROUND & AIMS: Lamivudine has been shown to improve liver disease and survival of hepatitis B virus patients on the orthotopic liver transplantation (OLT) waiting list, but liver failure might worsen in patients with drug resistance. Use of antiviral salvage therapy might decrease this risk. METHODS: We analyzed data from patients enrolled in the NIH HBV OLT cohort to study the effects of pretransplant antiviral therapy on transplant-free survival and survival without transplant. We also compared the clinical outcomes of those who did or did not develop antiviral failure (virologic breakthrough or genotypic resistance) while awaiting transplant. RESULTS: One hundred twenty-two eligible patients received antiviral therapy before OLT and were followed for a median of 40.5 months (range, 0.4-123.0 months) after initiation of antiviral therapy. Forty-four (36.1%) patients developed antiviral failure; all had lamivudine monotherapy as initial treatment. Forty-two patients started salvage therapy a median of 5 months after lamivudine failure; the median Model for End-Stage Liver Disease (MELD) score was 12. Twenty-one (50%) patients had a full response to salvage therapy. Eleven (26.2%) patients had a suboptimal virologic response but remained clinically compensated. Antiviral failure was not a significant predictor of transplant or death (P = .09) or death without transplant (P = .39). Multivariate predictors of transplant or death were high MELD score, hepatocellular carcinoma, and low albumin. High MELD score and low albumin were predictors of death without transplant. CONCLUSIONS: Antiviral failure in patients with HBV on the OLT waiting list did not impair clinical outcome if recognized early and if salvage therapy is promptly initiated.
Assuntos
Farmacorresistência Viral , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Falência Hepática/cirurgia , Transplante de Fígado , Inibidores da Transcriptase Reversa/uso terapêutico , Listas de Espera , Progressão da Doença , Feminino , Seguimentos , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Humanos , Falência Hepática/etiologia , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Estados UnidosAssuntos
Antineoplásicos/efeitos adversos , Falência Hepática/induzido quimicamente , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Idoso , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Benzamidas , Bilirrubina/sangue , Contagem de Células Sanguíneas , Índices de Eritrócitos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Falência Hepática/sangue , Falência Hepática/patologia , Masculino , Necrose , Tempo de Protrombina , Fatores de TempoRESUMO
Serum markers of liver fibrosis are difficult to validate, due to the sampling error and observer variability associated with percutaneous liver biopsies. Laparoscopic biopsy decreases sampling error and increases the reliability of histopathologic assessment. We prospectively evaluated the FIBROSpect(SM) II serum marker test for viral liver fibrosis against laparoscopic biopsies by studying 145 patients with chronic hepatitis B or C who underwent laparoscopy in a tertiary care setting. Serum samples obtained at biopsy were tested with FIBROSpect II to assess the degree of fibrosis. Multiple biopsies were obtained from each patient and scored blindly using the Batts-Ludwig system. An average biopsy stage was calculated and the performance of the test panel assessed. FIBROSpect II was able to rule in significant fibrosis (stages 2-4), with a likelihood ratio of 2.6. It correctly indicated absence of disease in 74% of stages 0-1 patients and correctly predicted significant disease in 67% of stages 2-4 patients. Test correlation was highest with Batts-Ludwig stages 3 (77%) and 4 (96%) and lowest with stage 2 (43%). Multiple biopsies from 52% of patients differed by at least 1 stage. In 13 patients (9%), cirrhosis was detected by laparoscopy but not histologically; in 4 (3%), a stage of 4 was obtained, but cirrhosis was not evident by laparoscopy. FIBROSpect II provided valuable additional information for assessing fibrosis. The discordance in fibrosis stage seen in multiple biopsies from the same patient underscores the need to consider all available information when assessing fibrosis. This study confirms and extends results of previous studies evaluating FIBROSpect II using percutaneous liver biopsy.
RESUMO
It is estimated that 43% of patients with nonalcoholic steatohepatitis (NASH) will progress to liver fibrosis or cirrhosis. Although NASH is more common in Hispanics, most studies have been conducted on Caucasians, and there is scarce information regarding ethnic differences in this disease. The aim of this study was to identify the independent predictors of cirrhosis in Hispanic patients with NASH. A retrospective case-control study was conducted on 80 patients with biopsy-proven NASH. Forty-two were Hispanic (study group) and 38 were Caucasians controlled for age and BMI (control group). Clinical, biochemical, and histologic features were analyzed for correlation with cirrhosis. There were no significant differences in demographic features between the two groups. In multivariate analysis, independent predictors of cirrhosis among Hispanic patients were age (OR, 1.07; 95% CI, 1.01-1.14) and AST/ALT ratio (OR, 10.56; 95% CI; 2.46-45.29), while independent predictors among non-Hispanic patients were age (OR, 1.085; 95% CI, 1.0-1.186), and diabetes mellitus (OR, 6.46; 95% CI, 1.19-35.07). In patients with NASH, predictors of cirrhosis varied according to ethnic background. Age was an independent predictor in both groups, however, AST/ALT ratio was found to be an independent predictor of cirrhosis only in Hispanic patients, and diabetes mellitus only in non-Hispanic patients.
Assuntos
Fígado Gorduroso/etnologia , Hispânico ou Latino , Cirrose Hepática/etnologia , Fatores Etários , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Índice de Massa Corporal , Complicações do Diabetes/complicações , Fígado Gorduroso/complicações , Fígado Gorduroso/enzimologia , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
We investigated the role of donor bone marrow cell (DBMC) infusions in immunosuppression withdrawal in adult liver transplantation. Patients enrolled were at least 3 years post-transplantation, with stable graft function. Forty-five (study group: G1) received DBMC, and 59 (control group: G2) did not. Immunosuppression was reduced by one third upon enrollment, by another third the second year of the study and was completely withdrawn the third year. Patient and graft survival were similar between the two groups. Although rejection episodes were significantly less in G1 the first 2 years of the study (35% vs. 57%, p = 0.016), there was no significant difference overall (74% vs. 81%, p = 0.14). Until February 2004, 20 patients, 10 in each group, were immunosuppression free for 1-3 years. Approximately 20% of long-term survivors of liver transplantation can successfully discontinue their immunosuppression. DBMC infusions, do not increase this likelihood.
Assuntos
Transplante de Medula Óssea , Rejeição de Enxerto/terapia , Terapia de Imunossupressão , Transplante de Fígado , Feminino , Humanos , Masculino , Fatores de Tempo , Doadores de TecidosRESUMO
Histopathologic assessment is considered essential for the differentiation of recurrent hepatitis C (RHC) from acute cellular rejection (ACR) after liver transplantation (LT); however, there is limited information regarding its reliability. The aim of this study was to determine the interobserver and intraobserver agreement of the histopathologic diagnosis of RHC vs. ACR, and to determine the reliability of specific histopathologic features for the differentiation of RHC from ACR. Liver biopsy specimens from 105 consecutive patients transplanted for hepatitis C virus (HCV)-related liver disease were studied retrospectively. All the biopsies were performed for evaluation of abnormal liver enzymes within the 1st year after LT. The slides were blindly coded and assessed by 5 liver-transplant pathologists, practicing at 3 medical centers. The pathologists were asked to render a diagnosis, and determine the severity of the disease. Four of the pathologists were asked to determine the presence and severity of 36 histopathologic features. A total of 34 of the samples were then blindly resubmitted to each of the 4 pathologists to determine the intraobserver agreement. There was a slight agreement (kappa = .12) among the 5 pathologists on the histopathologic diagnosis. All 5 pathologists were in agreement on the diagnosis of RHC in only 5 patients (5%) and on the diagnosis of ACR in only 2 patients (2%). The best agreement among any 4 pathologists was fair (kappa = .20). Slight to moderate agreement occurred on the main histological features considered to be important in the diagnosis of ACR. Intraobserver agreement ranged from slight (kappa = .19) to moderate (kappa = .42) among 4 pathologists. In conclusion, the histopathologic differentiation of RHC from ACR after LT had relatively low interobserver and intraobserver agreement rates, and hence showed low reliability. Histopathologic assessment should be used cautiously for the differentiation of RHC from ACR post-LT.