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BACKGROUND AND AIMS: There are limited data on the progression of liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in people with type 2 diabetes mellitus (T2DM) versus those without T2DM in biopsy-proven metabolic dysfunction-associated steatotic liver disease. We examined LSM progression in participants with T2DM versus those without T2DM in a large, prospective, multicenter cohort study. APPROACH AND RESULTS: This study included 1231 adult participants (62% female) with biopsy-proven metabolic dysfunction-associated steatotic liver disease who had VCTEs at least 1 year apart. LSM progression and regression were defined by a ≥20% increase and an upward or downward change, respectively, in the LSM category in the Baveno VII categories for compensated advanced chronic liver disease, compared between participants with T2DM (n = 680) versus no T2DM (n = 551) at baseline. The mean (±SD) age and body mass index were 51.8 (±12.0) years and 34.0 (±6.5) kg/m 2 , respectively. The median (IQR) time between the first and last VCTE measurements was 4.1 (2.5-6.5) years. Participants with T2DM had higher LSM progression at 4 years (12% vs. 10%), 6 years (23% vs. 16%), and 8 years (50% vs. 39%), p = 0.04. Using a multivariable Cox proportional hazards model adjusted for multiple confounders, the presence of T2DM remained an independent predictor of LSM progression (adjusted HR: 1.35, 95% CI: 1.01-1.81, p = 0.04). T2DM was not associated with LSM regression ( p = 0.71). Mean HbA1c was significantly associated with LSM progression ( p = 0.003) and regression ( p = 0.02). CONCLUSIONS: Using serial VCTE data from a multicenter study of participants with biopsy-proven metabolic dysfunction-associated steatotic liver disease, we demonstrate that T2DM and HbA1c are associated with LSM progression.
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Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied. AIMS: To determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp. METHODS: 25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and dysrhythmic ranges, was recorded using electrogastrography. RESULTS: Overall, vitamin D levels were low (< 30 ng/ml) in 288 of 513 (56.1%) patients with symptoms of Gp (206 of 376 (54.8%) patients with delayed gastric emptying (Gp) and 82 of 137 (59.9%) patients with symptoms of Gp and normal gastric emptying). Low vitamin D levels were associated with increased nausea and vomiting (P < 0.0001), but not with fullness or bloating subscores. Low vitamin D levels in patients with Gp were associated with greater meal retention at four hours (36% retention) compared with Gp patients with normal vitamin D levels (31% retention; P = 0.05). Low vitamin D in patients with normal gastric emptying was associated with decreased normal 3 cpm GMA before (P = 0.001) and increased tachygastria after WLST (P = 0.01). CONCLUSIONS: Low vitamin D levels are present in half the patients with symptoms of gastroparesis and are associated with nausea and vomiting and gastric neuromuscular dysfunction.
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BACKGROUND & AIMS: The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs). METHODS: Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status. RESULTS: In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p <0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p <0.01). CONCLUSIONS: Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD. IMPACT AND IMPLICATIONS: The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD.
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BACKGROUND AND AIMS: The patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship. APPROACH AND RESULTS: A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p =0.03, and p -value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p -value for interaction between PNPLA3 and each factor<0.01. CONCLUSIONS: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex.
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INTRODUCTION: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM). METHODS: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS). RESULTS: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF. DISCUSSION: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist.
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Técnicas de Imagem por Elasticidade , Infecções por HIV , Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Feminino , Estudos Prospectivos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Adulto , Cirrose Hepática/diagnóstico , Cirrose Hepática/sangue , Fígado/patologia , Fígado/diagnóstico por imagem , Valor Preditivo dos TestesRESUMO
Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with the enteric nervous system and influence gastrointestinal motility. Here we determine the human gastric muscle immunome and its changes in patients with idiopathic gastroparesis (IG). Single cell sequencing was performed on 26,000 CD45+ cells obtained from the gastric tissue of 20 subjects. We demonstrate 11 immune cell clusters with T cells being most abundant followed by myeloid cells. The proportions of cells belonging to the 11 clusters were similar between IG and controls. However, 9/11 clusters showed 578-11,429 differentially expressed genes. In IG, MM had decreased expression of tissue-protective and microglial genes and increased the expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in the activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis were upregulated. Patients with IG had a greater abundance of monocyte-like cells. These data further link immune dysregulation to the pathophysiology of gastroparesis.
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BACKGROUND & AIMS: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD. METHODS: A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG). RESULTS: PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% CI, 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013-1.026), CG (OR, 1.024; 95% CI, 1.018-1.030), and GG (OR, 1.03; 95% CI, 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m2 was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both). CONCLUSIONS: Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD.
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Aciltransferases , Índice de Massa Corporal , Diabetes Mellitus Tipo 2 , Lipase , Cirrose Hepática , Proteínas de Membrana , Hepatopatia Gordurosa não Alcoólica , Fosfolipases A2 Independentes de Cálcio , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Lipase/genética , Proteínas de Membrana/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Masculino , Adulto , Criança , Pessoa de Meia-Idade , Adolescente , Fatores Etários , Cirrose Hepática/genética , Adulto Jovem , Idoso , Genótipo , Predisposição Genética para DoençaRESUMO
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD. AIMS: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF). METHODS: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk. RESULTS: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk. CONCLUSIONS: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD.
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Infecções por HIV , Doenças Metabólicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Estados Unidos/epidemiologia , Adulto , Pessoa de Meia-Idade , Feminino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Prevalência , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/patologia , Obesidade/complicações , Doenças Metabólicas/complicações , Fígado/patologiaRESUMO
BACKGROUND: Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD. METHODS: Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components. RESULTS: In all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04). CONCLUSIONS: In children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.
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Dieta Saudável , Avaliação Nutricional , Humanos , Masculino , Criança , Feminino , Lipídeos , Açúcares , Peso CorporalRESUMO
BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction. OBJECTIVE: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed. METHODS: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene-set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls. RESULTS: While no SNP associations were detected at strict significance (p ≤ 5 × 10-8 ), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10-5 ), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10-7 ) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein-coding candidate genes. Gene-set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin-Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls). CONCLUSION: We report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory-motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.
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Gastroparesia , Estudo de Associação Genômica Ampla , Humanos , Gastroparesia/genética , Predisposição Genética para Doença , Dor AbdominalRESUMO
There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Fibrose , Biomarcadores , Biópsia/efeitos adversosRESUMO
Gastric emptying scintigraphy (GES) measures total gastric retention after a solid meal and can assess intragastric meal distribution (IMD). Water load satiety test (WLST) measures gastric capacity. Both IMD immediately after meal ingestion [ratio of proximal gastric counts after meal ingestion to total gastric counts at time 0 (IMD0)] and WLST (volume of water ingested over 5 min) are indirect measures of gastric accommodation. In this study, IMD0 and WLST were compared with each other and to symptoms of gastroparesis to gauge their clinical utility for assessing patients with symptoms of gastroparesis. Patients with symptoms of gastroparesis underwent GES to obtain gastric retention and IMD0, WLST, and filled out patient assessment of upper GI symptoms. A total of 234 patients with symptoms of gastroparesis were assessed (86 patients with diabetes, 130 idiopathic, 18 postfundoplication) and 175 (75%) delayed gastric emptying. Low IMD0 <0.568 suggesting initial rapid transit to the distal stomach was present in 8% and correlated with lower gastric retention, less heartburn, and lower volumes consumed during WLST. Low WLST volume (<238 mL) was present in 20% and associated with increased severity of early satiety, postprandial fullness, loss of appetite, and nausea. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. Thus, IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.NEW & NOTEWORTHY IMD0 and WLST were assessed for their clinical utility in assessing patients with symptoms of gastroparesis. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.
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Gastroparesia , Adulto , Humanos , Gastroparesia/diagnóstico por imagem , Gastroparesia/etiologia , Ingestão de Líquidos , Azia , Esvaziamento Gástrico , Náusea , CintilografiaRESUMO
BACKGROUND & AIMS: There are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies. METHODS: This study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM. RESULTS: The mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24). CONCLUSIONS: In this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Feminino , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Estudos de Coortes , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , BiópsiaRESUMO
BACKGROUND: Patients with gastroparesis and related disorders have symptoms including early satiety, postprandial fullness and bloating. Buspirone, a 5-HT1 receptor agonist, may improve fundic accommodation. AIM: To determine if buspirone treatment improves early satiety and postprandial fullness in patients with symptoms of gastroparesis. METHODS: This 4-week multi-centre clinical trial randomised patients with symptoms of gastroparesis and moderate-to-severe symptoms of fullness (Gastroparesis Cardinal Symptom Index [GCSI] early satiety/postprandial fullness subscore [ES/PPF]) to buspirone (10 mg orally) or placebo three times per day. The primary outcome was a change in the ES/PPF from baseline to 4 weeks. The primary analysis was per protocol intention-to-treat ANCOVA of between-group baseline vs. 4-week differences (DoD) in ES/PPF adjusted for baseline ES/PPF. Results are reported using both nominal and Bonferroni (BF) p values. RESULTS AND CONCLUSIONS: Ninety-six patients (47 buspirone, 49 placeboes; 92% female, 50% delayed gastric emptying, 39% diabetic) were enrolled. There was no between-groups difference in the 4-week ES/PPF primary outcome: -1.16 ± 1.25 (SD) on buspirone vs -1.03 ± 1.29 (SD) on placebo (mean DoD: -0.11 [95% CI: -0.68, 0.45]; p = 0.69). Buspirone performed better than placebo in patients with severe-to-very severe bloating at baseline compared to patients with none to moderate: (ES/PPF DoD = -0.65 vs. 1.58, pTX*GROUP = 0.003; pBF = 0.07). Among individual GCSI symptoms, only bloating appeared to improve with buspirone vs. placebo. CONCLUSIONS: Patients with moderate-to-severe early satiety/postprandial fullness and other symptoms of gastroparesis did not benefit from buspirone treatment to improve the ES/PPF primary outcome compared with placebo. There was a suggestion of the benefit of buspirone in patients with more severe bloating. TRIAL REGISTRATION: ClinicalTrials.gov NCT0358714285.
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Buspirona , Gastroparesia , Humanos , Feminino , Masculino , Buspirona/uso terapêutico , Gastroparesia/tratamento farmacológico , Gastroparesia/diagnóstico , Método Duplo-Cego , Esvaziamento GástricoRESUMO
BACKGROUND: Patients with gastroparesis (Gp) may need enteral nutrition (EN) or exclusive parenteral nutrition (PN). Among patients with Gp, we aimed to (1) identify the frequency of EN and exclusive PN use and (2) explore characteristics of patients using EN and/or exclusive PN compared with those using oral nutrition (ON), including changes over 48 weeks. METHODS: Patients with Gp underwent history and physical examination, gastric emptying scintigraphy, water load satiety testing (WLST), and questionnaires assessing gastrointestinal symptoms and quality of life (QOL). Patients were observed 48 weeks. RESULTS: Of 971 patients with Gp (idiopathic, 579; diabetic, 336; post-Nissen fundoplication, 51), 939 (96.7%) were using ON only, 14 (1.4%) using exclusive PN, and 18 (1.9%) using EN. Compared with patients receiving ON, patients receiving exclusive PN and/or EN were younger, had lower body mass index, and had greater symptom severity. Patients receiving exclusive PN and/or EN had lower physical QOL but not mental QOL or Gp-related QOL scores. Patients receiving exclusive PN and/or EN ingested less water during WLST but did not have worse gastric emptying. Of those who had been receiving exclusive PN and/or EN, 50% and 25%, respectively, resumed ON at 48-week follow-up. CONCLUSIONS: This study describes patients with Gp requiring exclusive PN and/or EN for nutrition support, who represent a small (3.3%) but important subset of patients with Gp. Unique clinical and physiological parameters are associated with this subset and provide insight into the use of nutrition support in Gp.
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Gastroparesia , Humanos , Gastroparesia/terapia , Qualidade de Vida , Apoio Nutricional , Nutrição Parenteral , Nutrição EnteralRESUMO
BACKGROUND AND AIMS: The NAFLD activity score was developed to measure histologic changes in NAFLD during therapeutic trials. Hepatocyte ballooning (HB) is the most specific feature in steatohepatitis diagnosis, yet the impact of variations in HB has not been incorporated. APPROACH AND RESULTS: Liver biopsies from patients enrolled in the NASH Clinical Research Network with an initial diagnosis of NASH or NAFL (n=1688) were evaluated to distinguish classic hepatocyte ballooning (cHB) from smaller, nonclassic hepatocyte ballooning (nHB), and also to designate severe ballooning and assign an extended hepatocyte ballooning (eB) score [0 points, no ballooning (NB); 1 point, few or many nHB; 2 points, few cHB; 3 points, many cHB; 4 points, severe cHB] to the biopsy assessment. The eB score was reproducible among NASH CRN liver pathologists (weighted kappa 0.76) and was significantly associated with older age (mean 52.1 y, cHB; 48.5 y, nHB, p<0.001), gender (72.3% female, cHB; 54.5% female, nHB, p<0.001), diabetes (49.8% diabetes, cHB; 28.2% diabetes, nHB, p<0.001), metabolic syndrome (68.5% metabolic syndrome, nHB; 50.2% metabolic syndrome, NB, p<0.001), and body mass index [33.2, 34.2, 35 mean body mass index (kg/m2); NB, nHB, and cHB, respectively, p<0.05]. Finally, fibrosis stage, as a marker of disease severity, was significantly correlated with the eB score (p<0.001). CONCLUSIONS: The eB score allows for a reproducible and more precise delineation of the range of ballooned hepatocyte morphology and corresponds with both clinical features of NASH and fibrosis stage.
Assuntos
Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Humanos , Feminino , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Relevância Clínica , Hepatócitos/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologiaRESUMO
Background There are no approved noninvasive tests (NIT) for the diagnosis of nonalcoholic steatohepatitis (NASH) and its histological phenotypes. Methods The FNIH-NIMBLE consortium tested 5 serum-based NIT panels for the following intended uses: NIS4: At-risk NASH, a composite of NASH with NAFLD activity score (NAS) ≥ 4 and fibrosis stage ≥ 2, OWLiver: NASH and NAS ≥ 4, enhanced liver fibrosis (ELF), PROC3 and Fibrometer VCTE: fibrosis stages ≥ 2, ≥ 3 or 4. Aliquots from a single blood sample obtained within 90 days of histological confirmation of NAFLD were tested. The prespecified performance metric tested for was a diagnostic AUROC greater than 0.7 and superiority to ALT for diagnosis of NASH or NAS ≥ 4 and to FIB-4 for fibrosis. Results A total of 1073 adults including NASH (n = 848), at-risk NASH (n = 539) and fibrosis stages 0-4 (n = 222, 114, 262, 277 and 198 respectively) were studied. The AUROC of NIS4 for at-risk NASH was 0.81 and superior to ALT and FIB4 (p < 0.001 for both). OWliver diagnosed NASH with sensitivity and specificity of 77.3% and 66.8% respectively. The AUROCs (95% CI) of ELF, PROC3 and Fibrometer VCTE respectively for fibrosis were as follows: ≥ stage 2 fibrosis [0.82 (0.8-0.85), 0.8 (0.77-0.83), and 0.84 (0.79-0.88)], ≥ stage 3 [0.83 (0.8-0.86), 0.76 (0.73-0.79), 0.85 (0.81-0.9), stage 4 [0.85 (0.81-0.89), 0.81 (0.77-0.85), 0.89 (0.84-0.95)]. ELF and Fibrometer VCTE were significantly superior to FIB-4 for all fibrosis endpoints (p < 0.01 for all). Conclusions These data support the further development of NIS4, ELF and Fibrometer VCTE for their intended uses.
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BACKGROUND: Patients with gastroparesis (GP) and functional dyspepsia (FD) have similar symptoms, but the pathophysiology of postprandial symptoms remains uncertain. AIMS: To compare symptoms and gastric myoelectrical activity (GMA) after liquid and solid test meals in patients with GP and FD. METHODS: Patients enrolled in the Gastroparesis Clinical Research Consortium Registry were studied. Clinical characteristics were measured with standard questionnaires. GP was determined by 4-h solid-phase gastric scintigraphy. GMA was measured using electrogastrography before and after ingestion of a water load or nutrient bar on separate days. Symptoms were measured on visual analog scales. GMA responses to the water load for individual patients were also determined. RESULTS: 284 patients with GP and 113 with FD were identified who ingested both test meals. Patients with GP and FD had similar maximal tolerated volumes of water [mean (SD) 378 (218) ml vs. 402 (226) ml, p = 0.23] and reported similar intensity of fullness, nausea, bloating, and abdominal discomfort after the test meals. Twenty-six percent and 19% of the patients with GP and FD, respectively, ingested subthreshold (<238 ml) volumes of water (p = 0.15). Gastric dysrhythmias were recorded in 66% of the GP and 65% of the FD patients after the water load. Symptoms and GMA were similar in both groups after ingestion of the nutrient bar. CONCLUSION: The similarity in GMA responses and symptoms after ingestion of solid or liquid test meals suggests GP and FD are closely related gastric neuromuscular disorders.
Assuntos
Dispepsia , Gastroparesia , Humanos , Esvaziamento Gástrico/fisiologia , Refeições , ÁguaRESUMO
BACKGROUND & AIMS: Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. METHODS: Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4). RESULTS: The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified. CONCLUSIONS: Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD. CLINICAL TRIAL NUMBER: Not applicable. IMPACT AND IMPLICATIONS: An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.