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1.
Artigo em Inglês | MEDLINE | ID: mdl-32360804

RESUMO

BACKGROUND & AIMS: Obese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH. METHODS: Twenty-one patients with early hepatic fibrosis (81% female; mean age, 54 years; average body mass index, 44 kg/m2) underwent magnetic resonance elastography (MRE) and endoscopic ultrasound with core liver biopsy collection at time IGB placement and removal at a single center from October 2016 through March 2018. The primary outcome measure was the changes in liver histology parameters after IGB, including change in nonalcoholic fatty liver disease activity score (NAS) and fibrosis score. We also evaluated changes in weight, body mass index, waist to hip ratio, aminotransaminases, fasting levels of lipids, fasting glucose, glycosylated hemoglobin, and MRE-detected liver stiffness. RESULTS: Six months after IGB, patients' mean total body weight loss was 11.7%±7.7%, with significant reductions in HbA1c (1.3%±0.5%) (P=.02). Waist circumference decreased by 14.4 ± 2.2 cm (P=.001). NAS improved in 18/20 patients (90%), with a median decrease of 3 points (range, 1-4 points ); 16/20 patients (80%) had improvements of 2 points or more. Fibrosis improved by 1.17 stages in 15% of patients, and MRE-detected fibrosis improved by 1.5 stages in 10/20 patients (50%). Half of patients reached endpoints approved by the Food and Drug Administration of for NASH resolution and fibrosis improvement. Percent total body weight loss did not correlate with reductions in NAS or fibrosis. Other than post-procedural pain (in 5% of patients), no serious adverse events were reported. CONCLUSION: In a prospective study, IGB facilitated significant metabolic and histologic improvements in NASH. IGB appears to be safe and effective for NASH management when combined with a prescribed diet and exercise program. ClinicalTrials.gov no: NCT02880189.

2.
Hepatology ; 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32246544

RESUMO

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as novel biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. APPROACH & RESULTS: EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end-stage liver disease (ESLD) due to cholestatic liver diseases and non-alcoholic steatohepatitis, decompensated alcoholic cirrhosis (AC) and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38X1011 /ml) compared to healthy controls (4.38X1010 /ml, p<0.0001), heavy drinkers (1.28X1011 /ml, p<0.0001), and ESLD (5.35X1010 /ml, p<0.0001) and decompensated AC (9.2X1010 /ml, p<0.0001) disease controls. Among AH subjects, EV concentration correlated with MELD score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high EV group and 90.0% in the low EV group (logrank p-value=0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared with healthy controls, heavy drinkers, ESLD and decompensated AC (p=0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. CONCLUSIONS: Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated alcoholic cirrhosis, and other etiologies of end-stage liver disease and predict 90-day survival permitting dynamic risk profiling.

3.
Transplantation ; 104(1): 211-221, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31283677

RESUMO

BACKGROUND: Posttransplant diabetes mellitus (PTDM) affects up to 50% of solid organ transplant recipients and compromises long-term outcomes. The goal of this study was to investigate how immunosuppressants affect gene expression in a manner that increases diabetes risk, by performing integrative analysis on publicly available, high-throughput gene expression data. METHODS: All high-throughput gene expression datasets of solid organ transplant recipients were retrieved from the Gene Expression Omnibus. Significantly dysregulated genes and pathways were determined, and those in common with type 2 diabetes were identified. THP-1 and HepG2 cells were exposed in vitro to tacrolimus, and validation of genes involved in insulin signaling and glucose metabolism was performed using specific arrays. These cells were then treated with the hypoglycemic agents, metformin, and insulin to assess for appropriate reversion of specific diabetogenic genes. RESULTS: Insulin signaling and secretion were the most commonly dysregulated pathways that overlapped with diabetes in transplant recipients. KRAS, GRB2, PCK2, BCL2L1, INSL3, DOK3, and PTPN1 were among the most significantly upregulated genes in both immunosuppression and diabetes subsets and were appropriately reverted by metformin as confirmed in vitro. CONCLUSIONS: We discovered that the significantly dysregulated genes in the context of immunosuppression are implicated in insulin signaling and insulin secretion, as a manifestation of pancreatic ß-cell function. In vitro validation confirmed key diabetes-related genes in the context of immunosuppression. Further analysis and in vitro validation revealed that metformin optimally reverts diabetogenic genes dysregulated in the context of immunosuppression. The optimal therapeutic management of posttransplant diabetes mellitus needs to be further investigated, taking into account the mechanistic impact of immunosuppressants.

4.
Hepatology ; 71(1): 334-345, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31342529

RESUMO

Cirrhotic cardiomyopathy (CCM) is cardiac dysfunction in patients with end-stage liver disease in the absence of prior heart disease. First defined in 2005 during the World Congress of Gastroenterology, CCM criteria consisted of echocardiographic parameters to identify subclinical cardiac dysfunction in the absence of overt structural abnormalities. Significant advancements in cardiovascular imaging over the past 14 years, including the integration of myocardial deformation imaging into routine clinical practice to identify subclinical cardiovascular dysfunction, have rendered the 2005 CCM criteria obsolete. Therefore, new criteria based on contemporary cardiovascular imaging parameters are needed. In this guidance document, assembled by a group of multidisciplinary experts in the field, new core criteria based on contemporary cardiovascular imaging parameters are proposed for the assessment of CCM. This document provides a critical assessment of the diagnosis of CCM and ongoing assessment aimed at improving clinical outcomes, particularly surrounding liver transplantation. Key points and practice-based recommendations for the diagnosis of CCM are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

5.
Am J Gastroenterol ; 114(11): 1764-1771, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31577570

RESUMO

OBJECTIVES: Cardiovascular (CV) disease is the top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Female sex is protective against CV disease. We aimed to determine whether female sex remains a protective factor against CV disease (myocardial infarction, angina, and stroke) in NAFLD. METHODS: We identified all adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014 and selected an age- and sex-matched (1:4) referent cohort from the general population. NAFLD was ascertained using a code-based algorithm with high validity tested by medical record review. The impact of female sex on incident CV events was examined using Cox proportional hazards regression analysis stratified by standard clinical risk factors. RESULTS: A total of 3,869 NAFLD and 15,209 age- and sex-matched referent subjects were identified. After a median follow-up time of 7 (range 1-20) years, 3,851 CV events were recorded. Female sex was protective for ischemic CV events in the general population (hazard ratio = 0.71, 95% confidence interval 0.62-0.80, P < 0.001), but the impact was significantly diminished among those with NAFLD (hazard ratio = 0.90, 95% confidence interval 0.74-1.08, P = 0.25), even after stratification by time-dependent CV risk factors and control for diagnostic testing (liver enzymes and ultrasound) during routine medical evaluations, as a surrogate of access to care. Among those with NAFLD, excess events were higher in women than in men: CV disease (18% vs 9%) and mortality (9% vs 6%). DISCUSSION: Women with NAFLD lose the CV protection conferred by the female sex, and their risk is underestimated by current estimating methods in clinical practice.

6.
Clin Transplant ; 33(8): e13629, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173653

RESUMO

BACKGROUND: Studies have suggested transplantation using older donor livers results in similar short-term outcomes as younger donor livers; however, little data exist on long-term patient/graft outcomes of the octogenarian liver recipient. METHODS: Retrospective data were collected from 2 centers, (Valencia, Spain and Rochester, MN, USA) of all recipients of octogenarian donor liver allografts from 2000 to 2011 with follow-up to 2016. The aim was to compare long-term patient/graft survival as well as metabolic outcomes of the recipient with the octogenarian liver vs younger than 60 years donor. RESULTS: 78 recipients of older liver allografts were compared to 78 matched controls. No difference in 10-year patient mortality was demonstrated (P = 0.074). Octogenarian livers were associated with 3-fold higher likelihood of graft failure (P = 0.002) but no increase in the risk of post-LT cardiovascular disease (P = 0.60), hypertension (P = 0.33), vascular complications (P = 0.53), or malignancy (P = 0.14). In multivariate analysis, elder livers remained a significant factor associated with rejection (P = 0.034) with a trend not reaching statistical significance for graft failure (P = 0.052). CONCLUSIONS: For appropriately selected recipients, receiving an octogenarian liver does not clearly influence patient survival but does impact early graft survival with a notable increase in early posttransplant rejection rates and re-transplantation. Over 1.5 decades, older allografts have not adversely affected metabolic outcomes.

7.
Hepatology ; 70(6): 2193-2203, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31034656

RESUMO

Sarcopenia is a common complication of cirrhosis and is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. Sarcopenia is associated with poor prognosis and increased mortality. How sarcopenia and muscle wasting relate to such poor outcomes requires looking beyond the overt muscle loss and at this entity as a systemic disease that affects muscles of vital organs including cardiac and respiratory muscles. This review explores the pathophysiological pathways and mechanisms that culminate in poor outcomes associated with sarcopenia. This provides a launching pad to identify potential targets for therapeutic intervention and optimization to improve patient outcomes.

8.
Aliment Pharmacol Ther ; 49(6): 807-813, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30714184

RESUMO

BACKGROUND: Sarcopenia is associated with both increased wait-list mortality and mortality following liver transplantation. AIMS: To determine the course of sarcopenia from transplant evaluation until 1 year post-transplant, and its implications on hospitalisation and mortality following liver transplantation. METHODS: Two hundred and ninety-three transplant recipients from 2002 to 2006 had pre-transplant CT scans analysed at the third lumbar region for sarcopenia, myosteatosis and abdominal visceral fat content. Half the recipients had post-transplant CT scan for interpretation (161/293). RESULTS: Sarcopenia was present in 146/293 (50%) of the patients pre-transplant. There was a significant decrease in muscle mass (loss 2.0 ± 4.9 cm2 /m2 ; P < 0.001), and an increase in myosteatosis while awaiting liver transplantation. There was no significant change in abdominal visceral fat. For every 1 cm2 /m2 decrease in muscle mass there was an increase in post-transplant length of stay by 0.36 days (P = 0.005). Post-transplant, 98/161 (61%) of patients with CT imaging had sarcopenia (25 de novo and 73 persistent), with continued increase in myosteatosis, lower Hounsfield units (-5.0 [IQR -8.6 to 0.1]; P < 0.001) and an increase in abdominal visceral fat (4.9 [IQR -4.4 to 15.6] cm2 /m2 ; P < 0.001). There was no statistically significant difference in 1-year mortality in patients with de novo sarcopenia compared to patients with sarcopenia both pre- and post-transplant (HR 1.88; P = 0.088). CONCLUSIONS: Sarcopenia progresses up to 1 year following liver transplantation and is associated with an increase in post-transplant length of stay.

9.
Liver Int ; 39(6): 1002-1013, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30716203

RESUMO

Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.

10.
Curr Opin Organ Transplant ; 24(2): 148-155, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30676402

RESUMO

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a common cause of mortality after liver transplantation. The transplant community is focused on improving long-term survival. Understanding the prevalence of CVD in liver transplant recipients, precipitating factors as well as prevention and management strategies is essential to achieving this goal. RECENT FINDINGS: CVD is the leading cause of death within the first year after transplant. Arrhythmia and heart failure are the most often cardiovascular morbidities in the first year after transplant which could be related to pretransplant diastolic dysfunction. Pretransplant diastolic dysfunction is reflective of presence of cirrhotic cardiomyopathy which is not as harmless as it was thought. Multiple cardiovascular risk prediction models have become available to aid management in liver transplant recipients. SUMMARY: A comprehensive prevention and treatment strategy is critical to minimize cardiovascular morbidity and mortality after liver transplant. Weight management and metabolic syndrome control are cornerstones to any prevention and management strategy. Bariatric surgery is an underutilized tool in liver transplant recipients. Awareness of 'metabolic-friendly' immunosuppressive regimens should be sought. Strict adherence to the cardiology and endocrine society guidelines with regard to managing metabolic derangements post liver transplantation is instrumental for CVD prevention until transplant specific recommendations can be made.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hepatopatias/cirurgia , Transplante de Fígado/efeitos adversos , Doenças Cardiovasculares/etiologia , Gerenciamento Clínico , Humanos , Fatores de Risco
11.
Psychosomatics ; 60(1): 56-65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30122643

RESUMO

BACKGROUND: Liver transplant candidates undergo psychosocial assessment as a component of their pretransplant evaluation. Global psychosocial assessment scales, including the Psychosocial Assessment of Candidates for Transplantation (PACT), capture and quantify these psychiatric and social variables. OBJECTIVE: Our primary aim was to assess for an association between global PACT score and survival in liver transplant recipients. METHODS: This retrospective cohort study examined records of all liver recipients at one U.S. Transplant Center from 2000 to 2012 with outcomes monitoring until 07/01/2016. We investigated for associations between the following variables and mortality: PACT score, age, gender, marital status, race, alcoholic liver disease (ALD), and body mass index (BMI). Statistical methods included Student's t-test, Wilcoxon rank sum test, chi-square, Fisher's exact test, Kaplan-Meier curve, and Cox proportional hazard models. RESULTS: Of 1040 liver recipients, 538 had a documented PACT score. Among these, PACT score was not associated with mortality. In women, a lower PACT score was associated with mortality (p = 0.003) even after adjustments for age, marital status, and BMI. Women with ALD had a 2-fold increased hazard of death (p = 0.012). Increasing age was associated with increased risk of death for the cohort as a whole (p = 0.019) and for men (p = 0.014). In men, being married and BMI were marginally protective (p = 0.10 and p = 0.13, respectively). CONCLUSIONS: Transplant psychosocial screening scales, specifically the PACT, identify psychosocial burden and may predict post-transplant outcomes in certain populations. In female liver recipients, lower PACT scores and ALD were associated with a greater risk of post-transplant mortality.


Assuntos
Cirrose Hepática Alcoólica/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Saúde Mental , Mortalidade , Apoio Social , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Estilo de Vida , Cirrose Hepática/cirurgia , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Psicologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
12.
Liver Transpl ; 25(1): 14-24, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30257063

RESUMO

Sarcopenia and frailty are commonly encountered in patients with end-stage liver disease and are associated with adverse clinical outcomes, including decompensation and wait-list mortality. The impact of these entities in patients with differing disease etiologies has not been elucidated. We aim to ascertain the change in their prevalence over time on the wait list and determine their impact on hospitalization, delisting, and wait-list survival, specifically for patients with nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD). Adult patients who were evaluated for their first liver transplant from 2014 to 2016 with a primary diagnosis of NASH (n = 136) or ALD (n = 129) were included. Computed tomography scans were used to determine the presence of sarcopenia and myosteatosis. Frailty was diagnosed using the Rockwood frailty index. Patients with NASH had a significantly lower prevalence of sarcopenia (22% versus 47%; P < 0.001) but a significantly higher prevalence of frailty (49% versus 34%; P = 0.03) when compared with patients with ALD at the time of listing. In patients with NASH, sarcopenia was not associated with adverse events, but a higher frailty score was associated with an increased length of hospitalization (P = 0.05) and an increased risk of delisting (P = 0.02). In patients with ALD, univariate analysis showed the presence of sarcopenia was associated with an increased risk of delisting (P = 0.01). In conclusion, sarcopenia and frailty occur with differing prevalence with variable impact on outcomes in wait-listed patients with NASH and ALD.


Assuntos
Doença Hepática Terminal/complicações , Fragilidade/epidemiologia , Hepatopatias Alcoólicas/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Sarcopenia/epidemiologia , Adulto , Idoso , Doença Hepática Terminal/patologia , Doença Hepática Terminal/cirurgia , Feminino , Fragilidade/diagnóstico , Fragilidade/etiologia , Humanos , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/cirurgia , Transplante de Fígado/normas , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Seleção de Pacientes , Prevalência , Estudos Retrospectivos , Sarcopenia/diagnóstico , Sarcopenia/etiologia , Listas de Espera/mortalidade
13.
Transplantation ; 103(1): 57-67, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30335694

RESUMO

Nonalcoholic steatohepatitis (NASH) is a growing indication for liver transplant whether the primary or secondary cause of liver disease, and it is expected to be the leading indication in the years to come. Nonalcoholic steatohepatitis recurs after transplant but the impact of the recurrence on allograft and patient outcomes is unclear. A group of multidisciplinary transplant practice providers convened at the International Liver Transplantation Society NASH consensus conference with the purpose of determining the current knowledge and future directions for understanding the recurrence rates, risk and management of NASH in the transplant allograft. Specific questions relating to posttransplant NASH were proposed and reviewed in detail with recommendations on future actions to fill the knowledge gaps.


Assuntos
Conferências de Consenso como Assunto , Cirrose Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/cirurgia , Prevenção Secundária/normas , Aloenxertos/patologia , Biópsia/normas , Comorbidade , Humanos , Fígado/patologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Guias de Prática Clínica como Assunto , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
14.
Clin Gastroenterol Hepatol ; 17(1): 54-64.e1, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30196155

RESUMO

BACKGROUND & AIMS: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. METHODS: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra-large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. RESULTS: We established LSM ranges for healthy individuals measured with both probes-these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. CONCLUSIONS: In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.


Assuntos
Antropometria , Elasticidade , Voluntários Saudáveis , Fígado/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Transplantation ; 103(1): 91-100, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29377876

RESUMO

BACKGROUND: Malignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database. METHODS: The Scientific Registry of Transplant Recipients database comprising all 108 412 LT recipients across the United States between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy. RESULTS: Mean age 51.9 ± 10.8 years, 64.6% male, 74.5% white, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1519 (14.0%) hematologic, and 4842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (hazard ratio [HR], 1.52; P < 0.001), male sex (HR, 1.28; P < 0.001), white race (compared with other races: HR, 1.45-2.04; P < 0.001), multiorgan transplant (HR, 1.35; P < 0.001), previous malignancy (HR, 1.34; P < 0.001), and alcoholic liver disease, autoimmune, nonalcoholic steatohepatitis (HR, 1.35; P < 0.001), and primary sclerosing cholangitis pre-LT (compared with hepatitis C virus, P < 0.001) were associated with higher risk of post-LT malignancy, but type of immunosuppression was not (P = NS). CONCLUSIONS: This large data set demonstrates the effects of ethnicity/race and etiologies of liver disease, particularly nonalcoholic steatohepatitis as additional risk factors for cancer after LT. Patients with these high-risk characteristics should be more regularly and diligently screened.


Assuntos
Grupo com Ancestrais do Continente Europeu , Hepatopatias/cirurgia , Transplante de Fígado/efeitos adversos , Neoplasias/etnologia , Adulto , Tomada de Decisão Clínica , Bases de Dados Factuais , Detecção Precoce de Câncer , Feminino , Humanos , Incidência , Hepatopatias/diagnóstico , Hepatopatias/etnologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/mortalidade , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
16.
Transplantation ; 103(1): e14-e21, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29994981

RESUMO

BACKGROUND: Hepatic steatosis is strongly associated with cardiovascular disease in the general population. Whether recurrent or de novo, it can occur in the allograft, but the impact on survival and long-term clinical outcomes remains unclear. In this study, we aim to determine both the frequency and impact of allograft steatosis on long-term posttransplant outcomes. METHODS: A retrospective review of 588 adult liver transplant (LT) recipients (1999-2006) was performed. Cox regression analysis (time-dependent) was used to evaluate differences in time to steatosis post-LT, patient survival, and cardiovascular outcomes. RESULTS: Mean age 51.9 ± 10.6 years, 64.6% males, underlying nonalcoholic steatohepatitis (NASH) (9.4%), previous tobacco (52%), pre-LT diabetes mellitus (30.3%), pre-LT hypertension (23.2%), and known cardiovascular disease (9.7%). Overall, 254 recipients developed allograft steatosis (at 10 years: 77.6% NASH recipients, 44.7% Non-NASH recipients). Risk factors for allograft steatosis were female sex (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.09-2.00; P = 0.014), hepatitis C virus diagnosis (HR, 2.49; 95% CI, 1.77-3.94; P < 0.001), and time-dependent BMI (per unit: HR, 1.08; 95% CI, 1.05-1.10; P < 0.001). Allograft steatosis was not associated with post-LT survival (P = 0.25) nor cardiovascular events (HR, 1.08; 95% CI, 0.73-1.59; P = 0.70). Underlying NASH associated with cardiovascular events (HR, 2.04; 95% CI, 1.37-3.04; P < 0.001). CONCLUSIONS: Allograft steatosis is common but not associated with survival or cardiovascular events in this study. Larger prospective studies are needed to better define the natural history of allograft steatosis.


Assuntos
Transplante de Fígado/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/cirurgia , Adulto , Aloenxertos , Doenças Cardiovasculares/epidemiologia , Comorbidade , Feminino , Humanos , Incidência , Transplante de Fígado/mortalidade , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/mortalidade , Prevalência , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
17.
Mayo Clin Proc ; 93(12): 1794-1802, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30522594

RESUMO

OBJECTIVE: To identify key predictors and survival outcomes of new-onset diabetes after transplant (NODAT) in liver transplant (LT) recipients by using the Scientific Registry of Transplant Recipients. PATIENTS AND METHODS: Data of all adult LT recipients between October 1, 1987, and March 31, 2016, were analyzed using various machine learning methods. These data were divided into training (70%) and validation (30%) data sets to robustly determine predictors of NODAT. The long-term survival of patients with NODAT relative to transplant recipients with preexisting diabetes and those without diabetes was assessed. RESULTS: Increasing age (odds ratio [OR], 1.01; 95% CI, 1.00-1.02; P≤.001), male sex (OR, 1.09; 95% CI, 1.05-1.13; P=.03), and obesity (OR, 1.13; 95% CI, 1.08-1.18; P<.001) were significantly associated with NODAT. Sirolimus as a primary immunosuppressant carried a 33% higher risk of NODAT than did tacrolimus (OR, 1.33; 95% CI, 1.22-1.45; P<.001) at 1 year after LT. Patients with NODAT had significantly decreased 10-year survival than did those without diabetes (63.0% vs 74.9%; P<.001), similar to survival in patients with diabetes before LT (58.9%). CONCLUSION: Using a machine learning approach, we found that older, male, and obese recipients are at especially higher risk of NODAT. Donor features do not affect risk. In addition, sirolimus-based immunosuppression is associated with a significantly higher risk of NODAT than other immunosuppressants. Most importantly, NODAT adversely affects long-term survival after LT in a manner similar to preexisting diabetes, indicating the need for more aggressive care and closer follow-up.


Assuntos
Diabetes Mellitus/epidemiologia , Imunossupressores/efeitos adversos , Transplante de Fígado/mortalidade , Sirolimo/efeitos adversos , Adulto , Fatores Etários , Algoritmos , Estudos Transversais , Diabetes Mellitus/etiologia , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Fatores de Risco , Fatores Sexuais , Doadores de Tecidos/estatística & dados numéricos , Estados Unidos/epidemiologia
18.
Cancer Med ; 7(12): 5870-5878, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30453389

RESUMO

BACKGROUND/AIMS: Hypothyroidism has been associated with hepatocellular carcinoma (HCC) incidence; however, the relationship between hypothyroidism and HCC patient outcomes is unclear. We investigated the impact of hypothyroidism on outcomes after liver transplantation for HCC. MATERIALS AND METHODS: We retrospectively studied HCC patients transplanted between January 2000 and December 2015. Hypothyroidism was defined as a thyroid-stimulating hormone (TSH) level continuously greater than 5 mIU/L, a documented history of hypothyroidism, or treatment with thyroid hormone replacement therapy. Multivariate Cox regression was used to assess the impact of hypothyroidism on overall survival (OS) and recurrence-free survival (RFS) adjusting for potential confounders. Subgroup analyses and interaction tests were conducted to compare the impact of hypothyroidism in different subgroups and assess for possible synergistic effects. Sensitivity analyses were performed among different cohorts to verify the stability of the results. RESULTS: A total of 343 HCC patients who underwent liver transplantation were included in the analysis. The primary analysis was conducted among 288 patients diagnosed with HCC prior to transplantation. Hypothyroidism was independently associated with worse OS and RFS, as was elevated TSH. The adjusted hazard ratio (AHR) of hypothyroidism was 2.45 (95% confidence interval [CI], 1.44-4.18) for OS and 5.54 (2.36, 13.01) for RFS. The AHR of TSH for OS was 1.05 (1.02, 1.09) and 1.08 (1.03, 1.13) for RFS. No interaction was found among different subgroups categorized by etiology and comorbidity. The results were stable to sensitivity analyses. CONCLUSION: Hypothyroidism is associated with poorer overall and recurrence-free survival of HCC patients receiving liver transplantation. These results require validation.


Assuntos
Carcinoma Hepatocelular/terapia , Hipotireoidismo/terapia , Neoplasias Hepáticas/terapia , Transplante de Fígado , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
19.
Ann Hepatol ; 17(5): 815-821, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30145562

RESUMO

INTRODUCTION AND AIM: Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited. OBJECTIVE: Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF. MATERIAL AND METHODS: Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed. RESULTS: Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred. CONCLUSIONS: Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Ribavirina/uso terapêutico , Simeprevir/uso terapêutico , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Idoso , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/diagnóstico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Ribavirina/efeitos adversos , Simeprevir/efeitos adversos , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico , Carga Viral
20.
Pancreatology ; 18(7): 691-699, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30061072

RESUMO

BACKGROUND: Acute pancreatitis (AP) associated with interferon-α or pegylated interferon-α (AP-IFN) has been described, although the causal relation certitude remains elusive. Some recent studies suggest definite causality, although the relation is grouped in class III of Badalov classification of drug-induced AP. OBJECTIVES: Perform systematic review of AP-IFN and assess causality. METHODS: Two reviewers independently evaluated the data and quality of studies extracted from multiple databases on March 13, 2017. Studies selection was based on a priori criteria. Naranjo scale, and Badalov classification were applied to determine causality. RESULTS: We identified 16 studies that reported AP-IFN with a total of 23 patients. Fifteen studies had moderate to good methodological quality. The frequency of AP-IFN was 7/3450 (0.2%). The median age of patients was 50 years. In most cases IFN was used for chronic hepatitis C. The latency between IFN and diagnosis of AP was (>30 days). AP was mild or moderately severe and improved with supportive management. No mortality was observed. Re-challenge was done in 5 patients and resulted in AP recurrence in 3 cases. Twenty-one cases were classified as probable and 2 cases as definitive according to Naranjo scale. Evaluations of studies confirm a status Ia for AP-IFN according to Badalov classification. CONCLUSION: AP-IFN is rare and has a probable or definite causal relation according to Naranjo scale. The evidence supports a class Ia of Badalov classification. Hypertriglyceridemia is not a contributing factor. IFN-induced AP is usually mild or moderately severe, and responds favorably to supportive management.


Assuntos
Interferon-alfa/efeitos adversos , Pancreatite/induzido quimicamente , Doença Aguda , Humanos
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