RESUMO
Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
Assuntos
Hematopoiese Clonal , Suscetibilidade a Doenças , Hepatite , Cirrose Hepática , Animais , Camundongos , Hematopoiese Clonal/genética , Hepatite/genética , Inflamação/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Razão de Chances , Progressão da DoençaRESUMO
Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.
Assuntos
Anti-Inflamatórios , Aspirina , Fígado Gorduroso , Fígado , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Aspirina/efeitos adversos , Aspirina/farmacologia , Aspirina/uso terapêutico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Método Duplo-Cego , Doença Hepática Terminal/etiologia , Doença Hepática Terminal/prevenção & controle , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Seguimentos , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Cirrose Hepática , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
PURPOSE: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis). METHODS: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). RESULTS: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD. CONCLUSION: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control.
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Acromegalia , Acromegalia/tratamento farmacológico , Adulto , Estudos Transversais , Hormônio do Crescimento/uso terapêutico , Humanos , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL. DESIGN: Cross-sectional. PATIENTS: 116 subjects: n = 55 receiving a somatostatin analog (SSA group); n = 29 receiving pegvisomant (PEG group); n = 32 active acromegaly on no medical therapy (ACTIVE group). MEASUREMENTS: Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics). RESULTS: There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52 ± 14 years, BMI 30 ± 6 kg/m2 , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9 ± 1.0) vs SSA and PEG, which did not differ from one another (0.5 ± 0.7 and 0.5 ± 0.7, P < .0001 vs ACTIVE). Eighty-three per cent of PEG previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%). There were no differences in the four QoL primary end-points (AcroQoL Global Score, SF-36 Physical Component Summary Score, SF-36 Mental Health Summary Score and GIQLI Global Score) between SSA and PEG. Higher HbA1c, BMI and IGF-1 Z-scores were associated with poorer QoL in several domains. CONCLUSION: Our data support a comparable QoL in patients receiving pegvisomant vs somatostatin analogs, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs.
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Acromegalia , Hormônio do Crescimento Humano , Acromegalia/tratamento farmacológico , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Receptores da Somatotropina , Somatostatina/uso terapêuticoRESUMO
BACKGROUND/OBJECTIVE: Less muscle mass has been associated with greater insulin resistance, but whether the association is independent of deleterious adipose depots in young adults with overweight/obesity who are at high risk for type 2 diabetes (T2DM) but are otherwise metabolically healthy is not known. The objective of this study was to determine whether muscle mass is independently associated with insulin sensitivity (IS) in young adults with overweight/obesity. SUBJECTS/METHODS: Cross-sectional Clinical Research Center study of 132 adults, 21-45yo, BMI ≥ 25 kg/m2 and metabolically healthy without T2DM. Primary independent variable: percent ideal appendicular lean mass (ALM) calculated as measured ALM divided by predicted ALM for age, weight, and height, calculated using validated NHANES data-based equation. Primary dependent variable: IS by Matsuda index. RESULTS: Mean age was 34.3 ± 6.8 years, and mean BMI 35.8 ± 5.8 kg/m2 (mean ± SD). Individuals in the highest % ideal ALM tertile had mean IS 45% higher than the lowest tertile [6.94 ± 0.85 vs 4.80 ± 0.56 (mean ± SEM), p = 0.008] (sex interaction p = 0.003). Men in the highest % ideal ALM tertile had mean IS twice the lowest tertile (5.47 ± 0.68 vs 2.68 ± 0.34, p = 0.001), which remained significant controlling for visceral/subcutaneous and intermuscular adipose tissue, and intramyocellular and intrahepatic lipids (p = 0.03). The association was not significant in women. CONCLUSIONS: Muscle mass is associated with IS independent of detrimental adipose depots in young men with overweight/obesity, at risk for T2DM but currently metabolically healthy. Muscle mass relative to sex, age, weight, and height-specific norms may be used to ascertain individual T2DM risk associated with low muscle mass.
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Resistência à Insulina/fisiologia , Músculo Esquelético/fisiologia , Obesidade , Tecido Adiposo/fisiopatologia , Adulto , População Negra/estatística & dados numéricos , Composição Corporal/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/química , Inquéritos Nutricionais , Obesidade/epidemiologia , Obesidade/fisiopatologia , Sobrepeso/epidemiologia , Sobrepeso/fisiopatologia , População Branca/estatística & dados numéricos , Adulto JovemAssuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Biópsia/métodos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVE: DSM-5 revised the diagnostic criteria for anorexia nervosa (AN) by eliminating the amenorrhea requirement, liberalizing weight and psychological criteria, and adding the formal diagnosis of "atypical AN" for individuals with AN psychological symptoms without low weight. We sought to determine whether bone density (BMD) is impaired in women diagnosed with AN using the new, more liberal, DSM-5 criteria. METHOD: Cross-sectional study of 168 women, 18 - 45y: (1) AN by DSM-IV (DSM-IV AN) (n = 37), (2) AN by DSM-5 but not DSM-IV criteria (DSM-5 AN) (n = 33), (3) atypical AN (ATYPICAL AN) (n = 77), (4) healthy comparison group (HC) (n = 21). Measurements included dual energy X-ray absorptiometry, Eating Disorder Examination-Questionnaire, Eating Disorder Inventory-2, Hamilton Depression and Anxiety Rating Scales. RESULTS: BMD Z-score <-1.0 was present in 78% of DSM-IV, 82% of DSM-5, and 69% of ATYPICAL. Mean Z-scores were comparably low in DSM-IV and DSM-5, intermediate in ATYPICAL, and highest in HC. Lack of prior low weight or amenorrhea was, but history of overweight/obesity was not, protective against bone loss. Mean lean mass and percent fat mass were significantly lower in all AN groups than HC. DSM-IV, DSM-5, and ATYPICAL had comparable psychopathology. DISCUSSION: Despite liberalizing diagnostic criteria, many women diagnosed with AN and atypical AN using DSM-5 criteria have low BMD. Presence or history of low weight and/or amenorrhea remain important indications for DXA. Loss of lean mass, in addition to fat mass, is present in all AN groups, and may contribute to low BMD. The deleterious effect of eating disorders on BMD extends beyond those with current low weight and amenorrhea. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:343-351).
Assuntos
Anorexia Nervosa/diagnóstico , Ansiedade/diagnóstico , Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Transtorno Depressivo/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Absorciometria de Fóton , Adolescente , Adulto , Amenorreia/fisiopatologia , Amenorreia/psicologia , Anorexia Nervosa/fisiopatologia , Anorexia Nervosa/psicologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Peso Corporal , Estudos Transversais , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: This study aimed to assess short- and long-term reproducibility of intrahepatic lipid (IHL) quantification by proton magnetic resonance spectroscopy (H-MRS) and computed tomography (CT). METHODS: Sixteen obese subjects underwent H-MRS using a single-voxel point-resolved single-voxel spectroscopy sequence at 3 T and noncontrast single-slice CT of the liver. Measurements were repeated after 6 weeks and 6 months. Clinical parameters (weight, activity, serum lipids) were collected. Short-term (baseline to 6 weeks) and long-term (baseline to 6 months) reproducibility of IHL was assessed by coefficient of variance (CV), SD, and intraclass correlation coefficient (ICC). RESULTS: Short-term reproducibility and long-term reproducibility of H-MRS were as follows: CV, 5.9% to 18.8%; SD, 0.7 to 1.9; and ICC, 0.998 to 0.995 (95% confidence interval, 0.942-0.999). Short-term reproducibility and long-term reproducibility of CT were as follows: CV, 4.4% to 14.2%; SD, 2.4 to 8.7; and ICC, 0.766 to 0.982 (95% confidence interval, 0.271-0.994). There was no significant change in clinical parameters (P > 0.3). CONCLUSIONS: Proton magnetic resonance spectroscopy and CT are reproducible methods for short- and long-term quantification of IHL content. Our results can guide sample size calculations for interventional and longitudinal studies.
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Metabolismo dos Lipídeos , Fígado/diagnóstico por imagem , Fígado/metabolismo , Obesidade/diagnóstico por imagem , Obesidade/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adulto , Biomarcadores/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To determine body composition predictors of skeletal integrity in overweight/obese subjects using dual energy X-ray absorptiometry (DXA). We hypothesized that visceral adiposity would be negatively, and lean mass positively, associated with DXA measures of skeletal integrity in obesity. MATERIALS AND METHODS: Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant and written informed consent was obtained. We studied 82 overweight or obese, but otherwise healthy premenopausal women and men of similar age who were part of a clinical trial (mean age: 37 ± 10 years, mean BMI: 34 ± 7 kg/m(2)). All subjects underwent DXA of the spine and hip for assessment of bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA), and of the whole body for the assessment of body composition, including estimated visceral adipose tissue (VAT). RESULTS: Sixty-three subjects (77 %) had normal BMD and 19 subjects (23 %) had osteopenia. There were strong age-, sex-, and BMD-independent positive associations between lean mass and HSA parameters (r = 0.50 to r = 0.81, p < 0.0001), whereas there was no association with TBS. There were strong age-, sex- and BMD-independent inverse associations between total fat and VAT mass and TBS (r = -0.60 and r = -0.72, p < 0.0001 for both correlations), whereas there were no associations with HSA parameters. CONCLUSION: Lean mass is a positive predictor of hip geometry, whereas fat and VAT mass are negative predictors of trabecular microarchitecture in overweight/obese subjects.
Assuntos
Composição Corporal , Densidade Óssea , Doenças Ósseas Metabólicas/fisiopatologia , Obesidade/diagnóstico por imagem , Obesidade/fisiopatologia , Medição de Risco/métodos , Absorciometria de Fóton , Adolescente , Adulto , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Boston/epidemiologia , Causalidade , Comorbidade , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/fisiopatologia , Pessoa de Meia-Idade , Obesidade/epidemiologia , Pré-Menopausa , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
Normal aging is linked to various endocrine gland changes, including changes in the adrenal glands. Aging is linked to alterations of the hypothalamic-pituitary-adrenal (HPA) axis, including an increase in cortisol levels, a disruption of the negative cortisol feedback, and attenuation of cortisol's diurnal pattern. In addition, secretion of aldosterone and adrenal androgens [dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)] from the adrenal cortex decreases with aging. In this review, we describe normal adrenal function, the adrenal response to stress and immunomodulation in aging individuals as well as the effects of adrenal aging on body composition, metabolic profile, bone health and cognition.
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Desidroepiandrosterona , Imunossenescência , Humanos , Hidrocortisona/metabolismo , Envelhecimento/fisiologia , Corticosteroides , Sulfato de DesidroepiandrosteronaRESUMO
CONTEXT: Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments. OBJECTIVE: We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD. METHODS: In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI ≥25 kg/m2 and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months. RESULTS: Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean ± SD: -5.2 ± 10.5% vs 3.8 ± 6.9%; P = .009), resulting in a net mean treatment effect of -8.9% (95% CI, -14.5 to -3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups. CONCLUSION: GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Obesidade/complicações , Obesidade/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Método Duplo-Cego , Fígado/metabolismoRESUMO
Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH. Methods: 16 patients with NAFLD (38% male, median (interquartile range): age 57 (48-64) years, BMI 37.5 (35.0-46.8) kg/m2) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify gray-level tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH. Results: By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67-100%) specificity and 80% (50-100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67-100%) specificity and 100% (50-100%) sensitivity, AUC 0.90. Conclusion: Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH.
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Physician parents encounter unique challenges in balancing new parenthood with work responsibilities, especially upon their return from parental leave. We designed a pilot program that incorporated 1:1 parental coaching to expectant and new physician parents and provided stipends for lactation support and help at home. Additional initiatives included launching a virtual new parent group during the COVID-19 pandemic and starting an emergency backup pump supplies program. There was positive feedback for our Parental Wellness Program (PWP), which was used to secure expanded funding. Pilot results showed that our program had a meaningful impact on parental wellness, morale, productivity, and lactation efforts.
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Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções por HIV/diagnóstico , HIV-1 , Pulmão/diagnóstico por imagem , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Idoso , Anti-Infecciosos/uso terapêutico , Diagnóstico Diferencial , Dispneia/etiologia , Feminino , Febre/etiologia , Infecções por HIV/complicações , Humanos , Pulmão/patologia , Oxigênio/sangue , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/microbiologia , Radiografia , Sudorese , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoAssuntos
Composição Corporal , Síndrome de Cushing/patologia , Sulfato de Desidroepiandrosterona/análise , Doenças das Glândulas Suprarrenais , Adulto , Idoso , Síndrome de Cushing/fisiopatologia , Feminino , Humanos , Doença Iatrogênica , Gordura Intra-Abdominal/patologia , Pessoa de Meia-Idade , Doenças da Hipófise , Gordura Subcutânea/patologiaRESUMO
Patients with obesity have a high prevalence of nonalcoholic fatty liver disease (NAFLD), representing a spectrum of simple steatosis to nonalcoholic steatohepatitis (NASH), without and with fibrosis. Understanding the etiology of NAFLD is clinically relevant since NAFLD is an independent risk factor for diabetes and cardiovascular disease. In addition, NASH predisposes patients to the development of cirrhosis and hepatocellular carcinoma, and NASH cirrhosis represents the fastest growing indication for liver transplantation in the United States. It is appreciated that multiple factors are involved in the development and progression of NAFLD. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) regulate metabolic, immune, and hepatic stellate cell function, and alterations in the production and function of GH is associated with obesity and NAFLD/NASH. Therefore, this review will focus on the potential role of GH and IGF1 in the regulation of hepatic steatosis, inflammation, and fibrosis.
Assuntos
Hormônio do Crescimento Humano , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Fibrose , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/metabolismoRESUMO
Objective: Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. Design: An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. Methods: In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. Results: Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. Conclusions: GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.
Assuntos
Densidade Óssea , Sobrepeso , Absorciometria de Fóton , Adulto , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológicoRESUMO
CONTEXT: Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD. OBJECTIVE: We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD. METHODS: This cross-sectional study included 102 adults (43% women; age 19-67; BMIâ ≥â 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined byâ ≥â 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was serum IGF-1 (LC/MS). RESULTS: There was no difference in mean age, BMI, or sex distribution in NAFLD vs controls. Mean (± SD) IHL was higher in NAFLD vs controls (21.8â ±â 13.3% vs 2.9â ±â 1.1%, Pâ <â 0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0â ±â 6.3 vs 15.4â ±â 11.2 ng/mL, Pâ =â 0.003), including after controlling for age, sex, visceral adipose tissue, and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (Pâ =â 0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher serum IGF-1 levels were associated with lower risk of liver fibrosis by Fibrosis-4 scores. CONCLUSION: Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Hormônio do Crescimento Humano , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Lipídeos , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Adulto JovemRESUMO
OBJECTIVE: The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). DESIGN: GEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1-4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1-3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. RESULTS: IGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. CONCLUSIONS: IGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH.