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There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.
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BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here, we investigate the prognostic value of HVPG in MASLD-related compensated ACLD (MASLD-cACLD). METHODS: This European multicentre study included patients with MASLD-cACLD characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. RESULTS: A total of 340 patients with MASLD-cACLD (56.2% male; median age 62 [55-68] years, median MELD 8 [7-9], 71.2% with diabetes) were included. Clinically significant portal hypertension (CSPH: i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in those with MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio [SHR] 5.13; p <0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (adjusted SHR per mmHg: 1.12, p <0.001). Liver-related mortality occurred in 37 patients at a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (adjusted SHR per mmHg: 1.20, p <0.001). CONCLUSION: HVPG measurement is of high prognostic value in MASLD-cACLD. In patients with MASLD-cACLD without CSPH, the short-term risk of decompensation is very low and liver-related mortality is rare, while the presence of CSPH substantially increases the risk of both. IMPACT AND IMPLICATIONS: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD patients, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in patients with MASLD-cACLD without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.
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BACKGROUND & AIMS: There is an unmet need for noninvasive tests to improve case-finding and aid primary care professionals in referring patients at high risk of liver disease. METHODS: A metabolic dysfunction-associated fibrosis (MAF-5) score was developed and externally validated in a total of 21,797 individuals with metabolic dysfunction in population-based (National Health and Nutrition Examination Survey 2017-2020, National Health and Nutrition Examination Survey III, and Rotterdam Study) and hospital-based (from Antwerp and Bogota) cohorts. Fibrosis was defined as liver stiffness ≥8.0 kPa. Diagnostic accuracy was compared with FIB-4, nonalcoholic fatty liver disease fibrosis score (NFS), LiverRisk score and steatosis-associated fibrosis estimator (SAFE). MAF-5 was externally validated with liver stiffness measurement ≥8.0 kPa, with shear-wave elastography ≥7.5 kPa, and biopsy-proven steatotic liver disease according to Metavir and Nonalcoholic Steatohepatitis Clinical Research Network scores, and was tested for prognostic performance (all-cause mortality). RESULTS: The MAF-5 score comprised waist circumference, body mass index (calculated as kg / m2), diabetes, aspartate aminotransferase, and platelets. With this score, 60.9% was predicted at low, 14.1% at intermediate, and 24.9% at high risk of fibrosis. The observed prevalence was 3.3%, 7.9%, and 28.1%, respectively. The area under the receiver operator curve of MAF-5 (0.81) was significantly higher than FIB-4 (0.61), and outperformed the FIB-4 among young people (negative predictive value [NPV], 99%; area under the curve [AUC], 0.86 vs NPV, 94%; AUC, 0.51) and older adults (NPV, 94%; AUC, 0.75 vs NPV, 88%; AUC, 0.55). MAF-5 showed excellent performance to detect liver stiffness measurement ≥12 kPa (AUC, 0.86 training; AUC, 0.85 validation) and good performance in detecting liver stiffness and biopsy-proven liver fibrosis among the external validation cohorts. MAF-5 score >1 was associated with increased risk of all-cause mortality in (un)adjusted models (adjusted hazard ratio, 1.59; 95% CI, 1.47-1.73). CONCLUSIONS: The MAF-5 score is a validated, age-independent, inexpensive referral tool to identify individuals at high risk of liver fibrosis and all-cause mortality in primary care populations, using simple variables.
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Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática , Valor Predictivo de las Pruebas , Humanos , Masculino , Femenino , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/patología , Cirrosis Hepática/etiología , Persona de Mediana Edad , Medición de Riesgo , Anciano , Pronóstico , Índice de Masa Corporal , Factores de Riesgo , Circunferencia de la Cintura , Encuestas Nutricionales , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patología , Adulto , Aspartato Aminotransferasas/sangre , Recuento de Plaquetas , Hígado/patología , Hígado/diagnóstico por imagen , Países Bajos/epidemiología , Biopsia , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: The Baveno VI criteria have set the stage for noninvasive assessment of compensated advanced chronic liver disease (ACLD). The algorithm combining liver stiffness measurement (LSM, <20 kPa) and platelet count (>150,000/µL) safely avoids screening endoscopy for varices needing treatment (VNT) but identifies only a relatively low number of patients. We aimed to evaluate the value of spleen stiffness measurement (SSM) using spleen-dedicated elastography in ruling out VNT. METHODS: In this real-life multicenter retrospective derivation-validation cohort, all consecutive patients with ACLD (defined by LSM ≥10 kPa) with available upper endoscopy, laboratory results, spleen diameter, LSM, and SSM measured with spleen-dedicated transient elastography were included. VNT were defined as medium-to-large varices or small varices with red spots. RESULTS: In the derivation cohort (n = 201, 11.9% VNT), SSM demonstrated excellent capability at identifying VNT (area under the receiver operating characteristic curve [AUROC] 0.88), outperforming LSM (AUROC 0.77, P = 0.03) and platelets (AUROC 0.73, P = 0.002). In comparison with Baveno VI criteria (33.8% spared endoscopies), the sequential Baveno VI plus SSM and a novel spleen size and stiffness model were able to increase the number of patients avoiding endoscopy (66.2% and 71.1%, respectively) without missing more than 5% of VNT. These findings were confirmed in an external validation cohort of patients with more advanced liver disease (n = 176, 34.7% VNT) in which the number of spared endoscopies tripled (27.3% and 31.3% for SSM-based algorithms) compared with Baveno VI criteria (8.5%). DISCUSSION: Spleen stiffness-based algorithms are superior to Baveno VI criteria in ruling out VNT in patients with ACLD and double the number of patients avoiding screening endoscopy.
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Algoritmos , Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas , Bazo , Humanos , Bazo/diagnóstico por imagen , Bazo/patología , Femenino , Masculino , Persona de Mediana Edad , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/diagnóstico , Estudios Retrospectivos , Recuento de Plaquetas , Anciano , Cirrosis Hepática/complicaciones , Curva ROC , Hepatopatías/complicaciones , Hepatopatías/diagnóstico por imagenRESUMEN
BACKGROUND: Obesity is linked to several health complication, including Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD). Adipose tissue hypoxia has been suggested as an important player in the pathophysiological mechanism leading to chronic inflammation in obesity, and in the progression of MASLD. The study aims to investigate the effect of progressive obesity on adipose and liver tissue hypoxia. METHODS: Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) or control diet (CD) for 4, 8, 12, 16 and 20 weeks. Serum ALT, AST and lipid levels were determined, and glucose and insulin tolerance testing was performed. Liver, gonadal and subcutaneous adipose tissue was assessed histologically. In vivo tissue pO2 measurements were performed in gonadal adipose tissue and liver under anesthesia. A PCR array for hypoxia responsive genes was performed in liver and adipose tissue. The main findings in the liver were validated in another diet-induced MASLD mice model, the choline-deficient L-amino acid defined high-fat diet (CDAHFD). RESULTS: HFHFD feeding induced a progressive obesity, dyslipidaemia, insulin resistance and MASLD. In vivo pO2 was decreased in gonadal adipose tissue after 8 weeks of HFHFD compared to CD, and decreased further until 20 weeks. Liver pO2 was only significantly decreased after 16 and 20 weeks of HFHFD. Gene expression and histology confirmed the presence of hypoxia in liver and adipose tissue. Hypoxia could not be confirmed in mice fed a CDAHFD. CONCLUSION: Diet-induced obesity in mice is associated with hypoxia in liver and adipose tissue. Adipose tissue hypoxia develops early in obesity, while liver hypoxia occurs later in the obesity development but still within the early stages of MASLD. Liver hypoxia could not be directly confirmed in a non-obese liver-only MASLD mice model, indicating that obesity-related processes such as adipose tissue hypoxia are important in the pathophysiology of obesity and MASLD.
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Hígado Graso , Obesidad , Masculino , Ratones , Animales , Ratones Endogámicos C57BL , Obesidad/metabolismo , Hígado/metabolismo , Hígado Graso/metabolismo , Tejido Adiposo/metabolismo , Dieta Alta en Grasa/efectos adversos , Hipoxia/metabolismoRESUMEN
Background & Aims: The epidemiology of non-alcoholic fatty liver disease (NAFLD) in people with type 1 diabetes (T1D) is not yet elucidated. This study aimed to assess the diagnostic accuracy of non-invasive tests for NAFLD, to investigate the prevalence and severity of NAFLD, and to search for factors contributing to NAFLD in people with T1D. Methods: In this prospective cohort study, we consecutively screened 530 adults with T1D from a tertiary care hospital, using ultrasound (US), vibration-controlled transient elastography equipped with liver stiffness measurement (LSM) and controlled attenuation parameter, and the fatty liver index. Magnetic resonance spectroscopy (MRS) was performed in a representative subgroup of 132 individuals to validate the diagnostic accuracy of the non-invasive tests. Results: Based on MRS as reference standard, US identified individuals with NAFLD with an AUROC of 0.98 (95% CI 0.95-1.00, sensitivity: 1.00, specificity: 0.96). The controlled attenuation parameter was also accurate with an AUROC of 0.85 (95% CI 0.77-0.93). Youden cut-off was ≥270 dB/m (sensitivity: 0.90, specificity: 0.74). The fatty liver index yielded a similar AUROC of 0.83 (95% CI 0.74-0.91), but the conventional cut-off used to rule in (≥60) had low sensitivity and specificity (0.62, 0.78). The prevalence of NAFLD in the overall cohort was 16.2% based on US. Metabolic syndrome was associated with NAFLD (OR: 2.35 [1.08-5.12], p = 0.031). The overall prevalence of LSM ≥8.0 kPa indicating significant fibrosis was 3.8%, but reached 13.2% in people with NAFLD. Conclusions: NAFLD prevalence in individuals with T1D is 16.2%, with approximately one in 10 featuring elevated LSM. US-based screening could be considered in people with T1D and metabolic syndrome. Impact and Implications: We aimed to report on the prevalence, disease severity, and risk factors of NAFLD in type 1 diabetes (T1D), while also tackling which non-invasive test for NAFLD is the most accurate. We found that ultrasound is the best test to diagnose NAFLD. NAFLD prevalence is 16.2%, and is associated with metabolic syndrome and BMI. Elevated liver stiffness indicating fibrosis is overall not prevalent in people with T1D (3.8%), but it reaches 13.2% in those with T1D and NAFLD.
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Immunohistochemical stains (IHC) reveal differences between liver lobule zones in health and disease, including nonalcoholic fatty liver disease (NAFLD). However, such differences are difficult to accurately quantify. In NAFLD, the presence of lipid vacuoles from macrovesicular steatosis further hampers interpretation by pathologists. To resolve this, we applied a zonal image analysis method to measure the distribution of hypoxia markers in the liver lobule of steatotic livers.The hypoxia marker pimonidazole was assessed with IHC in the livers of male C57BL/6 J mice on standard diet or choline-deficient L-amino acid-defined high-fat diet mimicking NAFLD. Another hypoxia marker, carbonic anhydrase IX, was evaluated by IHC in human liver tissue. Liver lobules were reconstructed in whole slide images, and staining positivity was quantified in different zones in hundreds of liver lobules. This method was able to quantify the physiological oxygen gradient along hepatic sinusoids in normal livers and panlobular spread of the hypoxia in NAFLD and to overcome the pronounced impact of macrovesicular steatosis on IHC. In a proof-of-concept study with an assessment of the parenchyma between centrilobular veins in human liver biopsies, carbonic anhydrase IX could be quantified correctly as well.The method of zonated quantification of IHC objectively quantifies the difference in zonal distribution of hypoxia markers (used as an example) between normal and NAFLD livers both in whole liver as well as in liver biopsy specimens. It constitutes a tool for liver pathologists to support visual interpretation and estimate the impact of steatosis on IHC results.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Masculino , Humanos , Anhidrasa Carbónica IX , Inmunohistoquímica , Ratones Endogámicos C57BL , Hígado/patología , Hipoxia/patologíaRESUMEN
BACKGROUND & AIMS: In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. METHODS: A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS: Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). CONCLUSIONS: Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. IMPACT AND IMPLICATIONS: We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.
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Diagnóstico por Imagen de Elasticidad , Hipertensión Portal , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Hipertensión Portal/complicaciones , Hipertensión Portal/diagnóstico , Presión Portal , Recuento de Plaquetas , BilirrubinaRESUMEN
BACKGROUND & AIMS: Intrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH). METHODS: The effects of endothelin-1 (ET-1), angiotensin II (ATII) and thromboxane A2 (TxA2) agonism and antagonism were studied by in situ ex vivo liver perfusion and preventive/therapeutic treatment experiments in a methionine-choline-deficient diet model of steatosis. Furthermore, important results were validated in Zucker fatty rats after 4 or 8 weeks of high-fat high-fructose diet feeding. In vivo systemic and portal pressures, ex vivo transhepatic pressure gradients (THPG) and transaminase levels were measured. Liver tissue was harvested for structural and mRNA analysis. RESULTS: The THPG and consequent portal pressure were significantly increased in both models of steatosis and in NASH. ET-1, ATII and TxA2 increased the THPG even further. Bosentan (ET-1 receptor antagonist), valsartan (ATII receptor blocker) and celecoxib (COX-2 inhibitor) attenuated or even normalised the increased THPG in steatosis. Simultaneously, bosentan and valsartan treatment improved transaminase levels. Moreover, bosentan was able to mitigate the degree of steatosis and restored the disrupted microvascular structure. Finally, beneficial vascular effects of bosentan endured in NASH. CONCLUSIONS: Antagonism of vasoconstrictive mediators improves intrahepatic vascular function. Both ET-1 and ATII antagonists showed additional benefit and bosentan even mitigated steatosis and structural liver damage. In conclusion, vasoconstrictive antagonism is a potentially promising therapeutic option for the treatment of early NAFLD. LAY SUMMARY: In non-alcoholic fatty liver disease (NAFLD), hepatic blood flow is impaired and the blood pressure in the liver blood vessels is increased as a result of an increased response of the liver vasculature to vasoconstrictors. Using drugs to block the constriction of the intrahepatic vasculature, the resistance of the liver blood vessels decreases and the increased portal pressure is reduced. Moreover, blocking the vasoconstrictive endothelin-1 pathway restored parenchymal architecture and reduced disease severity.
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BACKGROUND & AIMS: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension-related decompensation in patients with advanced NAFLD (aNAFLD). METHODS: Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels. RESULTS: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P = .019) than in the aHCV group. For any of the HVPG cutoff analyzed (<10, 10-12, or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD group than in the aHCV group. CONCLUSIONS: Patients with aNAFLD have higher prevalence of portal hypertension-related decompensation at any value of HVPG as compared with aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed.
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Enfermedad Hepática en Estado Terminal , Hepatitis C , Hipertensión Portal , Enfermedad del Hígado Graso no Alcohólico , Estudios Transversales , Enfermedad Hepática en Estado Terminal/complicaciones , Hepatitis C/complicaciones , Humanos , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Presión Portal , ARN , Índice de Severidad de la EnfermedadRESUMEN
Autoimmune destruction of pancreatic ß-cells results in the permanent loss of insulin production in type 1 diabetes (T1D). The daily necessity to inject exogenous insulin to treat hyperglycemia leads to a relative portal vein insulin deficiency and potentiates hypoglycemia which can induce weight gain, while daily fluctuations of blood sugar levels affect the hepatic glycogen storage and overall metabolic control. These, among others, fundamental characteristics of T1D are associated with the development of two distinct, but in part clinically similar hepatopathies, namely non-alcoholic fatty liver disease (NAFLD) and glycogen hepatopathy (GlyH). Recent studies suggest that NAFLD may be increasingly common in T1D because more people with T1D present with overweight and/or obesity, linked to the metabolic syndrome. GlyH is a rare but underdiagnosed complication hallmarked by extremely brittle metabolic control in, often young, individuals with T1D. Both hepatopathies share clinical similarities, troubling both diagnosis and differentiation. Since NAFLD is increasingly associated with cardiovascular and chronic kidney disease, whereas GlyH is considered self-limiting, awareness and differentiation between both condition is important in clinical care. The exact pathogenesis of both hepatopathies remains obscure, hence licensed pharmaceutical therapy is lacking and general awareness amongst physicians is low. This article aims to review the factors potentially contributing to fatty liver disease or glycogen storage disruption in T1D. It ends with a proposal for clinicians to approach patients with T1D and potential hepatopathy.
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BACKGROUND & AIMS: Studies exploring the relationship between muscle fat content and non-alcoholic fatty liver disease (NAFLD) are scarce. Herein, we aimed to evaluate the association of muscle mass and fatty infiltration with biopsy-assessed NAFLD in patients with obesity. METHODS: At inclusion (n = 184) and 12 months after a dietary intervention (n = 15) or bariatric surgery (n = 24), we evaluated NAFLD by liver biopsy, and skeletal muscle mass index (SMI) by CT (CT-SMI) or bioelectrical impedance analysis (BIA-SMI). We developed an index to evaluate absolute fat content in muscle (skeletal muscle fat index [SMFI]) from CT-based psoas muscle density (SMFIPsoas). RESULTS: Muscle mass was higher in patients with NAFLD than in those without (CT-SMI 56.8 ± 9.9 vs. 47.4 ± 6.5 cm2/m2, p <0.0001). There was no association between sarcopenia and non-alcoholic steatohepatitis (NASH). SMFIPsoas was higher in NASH ≥F2 and early NASH F0-1 than in NAFL (78.5 ± 23.6 and 73.1 ± 15.6 vs. 61.2 ± 12.6, p <0.001). A 1-point change in the score for any of the individual cardinal NASH features (i.e. steatosis, inflammation or ballooning) was associated with an increase in SMFIPsoas (all p <0.05). The association between SMFIPsoas and NASH was highly significant even after adjustment for multiple confounders (all p <0.025). After intervention (n = 39), NASH improvement, defined by NAFLD activity score <3 or a 2-point score reduction, was achieved in more than 75% of patients (n = 25 or n = 27, respectively) that had pre-established NASH at inclusion (n = 32) and was associated with a significant decrease in SMFIPsoas (p <0.001). Strikingly, all patients who had ≥11% reduction in SMFIPsoas achieved NASH improvement (14/14, p <0.05). CONCLUSIONS: Muscle fat content, but not muscle mass, is strongly and independently associated with NASH. All individuals who achieved a ≥11% decrease in SMFIPsoas after intervention improved their NASH. These data indicate that muscle fatty infiltration could be a potential marker for (and perhaps a pathophysiological contributor to) NASH. LAY SUMMARY: The fat content in skeletal muscles is highly reflective of the severity of non-alcoholic fatty liver disease (NAFLD) in patients with morbid obesity. In particular, muscle fat content is strongly associated with non-alcoholic steatohepatitis (NASH) and decreases upon NASH improvement. These data indicate that muscle fatty infiltration could be a marker and possible pathophysiological contributor to NASH.
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Tejido Adiposo/anomalías , Enfermedad del Hígado Graso no Alcohólico/etiología , Tejido Adiposo/fisiopatología , Adulto , Análisis de Varianza , Estudios de Cohortes , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Músculos/anomalías , Músculos/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Oportunidad RelativaRESUMEN
A Correction to this paper has been published: https://doi.org/10.1038/s41551-020-0569-y.
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Background and Aims: Non-alcoholic steatohepatitis (NASH) is a multisystem condition, involving the liver, adipose tissue, and immune system. Regulatory T (Treg) cells are a subset of T cells that exert an immune-controlling effect. Previously, a reduction of Treg cells in the visceral adipose tissue (VAT) was shown to be associated with a more severe degree of liver disease. We aimed to correct this immune disruption through adoptive cell transfer (ACT) of Treg cells. Methods: Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) for 20 weeks. Treg cells were isolated from the spleens of healthy 8 to 10-week-old C57BL/6J mice and were adoptively transferred to HFHFD-fed mice. PBS-injected mice served as controls. Plasma ALT and lipid levels were determined. Liver and adipose tissue were assessed histologically. Cytotoxic T (Tc), Treg, T helper (Th) 1 and Th17 cells were characterized in VAT, liver, subcutaneous adipose tissue (SAT), blood, and spleen via flow cytometry. Gene expression analysis was performed in SAT and VAT of mice fed either the HFHFD or a control diet for 10-32 weeks. Results: ACT increased Treg cells in SAT, but not in any of the other tissues. Moreover, the ACT induced a decrease in Th1 cells in SAT, liver, blood, and spleen. Higher plasma ALT levels and a higher degree of steatosis were observed in ACT mice, whereas the other HFHFD-induced metabolic and histologic disruptions were unaffected. Expression analysis of genes related to Treg-cell proliferation revealed a HFHFD-induced decrease in all investigated genes in the SAT, while in the VAT the expression of these genes was largely unaffected, except for a decrease in Pparg. Conclusion: ACT of Treg cells in HFHFD-fed mice exacerbated hepatic steatosis, which was possibly related to the increase of Treg cells in the SAT and/or the general decrease in Th1 cells. Moreover, the HFHFD-induced decrease in Pparg expression appeared critical in the decrease of Treg cells at the level of the VAT and the inability to replenish the amount of Treg cells by the ACT, while the mechanism of Treg cell accumulation at the level of the SAT remained unclear.
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Traslado Adoptivo/métodos , Grasa Intraabdominal/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Grasa Subcutánea/inmunología , Linfocitos T Reguladores/trasplante , Animales , Dieta Alta en Grasa/efectos adversos , Fructosa/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiologíaRESUMEN
Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.
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Lipofuscina/metabolismo , Hepatopatías/diagnóstico por imagen , Hepatopatías/patología , Animales , Biomarcadores/metabolismo , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Fluorescencia , Humanos , Lipodistrofia/diagnóstico por imagen , Lipodistrofia/metabolismo , Lipodistrofia/patología , Hígado/diagnóstico por imagen , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Hepatopatías/metabolismo , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Imagen Óptica , Espectroscopía Infrarroja CortaRESUMEN
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a multisystem condition, implicating liver and adipose tissue. Although the general involvement of the innate and adaptive immune system has been established, we aimed to define the exact role of the functionally diverse T-cell subsets in NASH pathogenesis through diet reversal and immunologic modulation. METHODS: Multiple experimental set-ups were used in 8-week-old C57BL/6J mice, including prolonged high-fat high-fructose diet (HFHFD) feeding, diet reversal from HFHFD to control diet, and administration of anti-CD8a and anti-interleukin 17A antibodies. Plasma alanine aminotransferase, glucose, and lipid levels were determined. Liver and adipose tissue were assessed histologically. Cytotoxic T (Tc), regulatory T, T helper (Th) 1, and Th17 cells were characterized in liver and visceral adipose tissue (VAT) via flow cytometry and RNA analysis. RESULTS: HFHFD feeding induced the metabolic syndrome and NASH, which coincided with an increase in hepatic Th17, VAT Tc, and VAT Th17 cells, and a decrease in VAT regulatory T cells. Although diet reversal induced a phenotypical metabolic and hepatic normalization, the observed T-cell disruptions persisted. Treatment with anti-CD8a antibodies decreased Tc cell numbers in all investigated tissues and induced a biochemical and histologic attenuation of the HFHFD-induced NASH. Conversely, anti-interleukin 17A antibodies decreased hepatic inflammation without affecting other features of NASH or the metabolic syndrome. CONCLUSIONS: HFHFD feeding induces important immune disruptions in multiple hepatic and VAT T-cell subsets, refractory to diet reversal. In particular, VAT Tc cells are critically involved in NASH pathogenesis, linking adipose tissue inflammation to liver disease.
Asunto(s)
Factores Inmunológicos/farmacología , Grasa Intraabdominal/patología , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD8/antagonistas & inhibidores , Antígenos CD8/metabolismo , Dieta Alta en Grasa/efectos adversos , Azúcares de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Fructosa/efectos adversos , Humanos , Factores Inmunológicos/uso terapéutico , Interleucina-17/antagonistas & inhibidores , Interleucina-17/metabolismo , Grasa Intraabdominal/citología , Grasa Intraabdominal/inmunología , Hígado/citología , Hígado/inmunología , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/terapia , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.
Asunto(s)
Diabetes Mellitus Tipo 2/inmunología , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Obesidad/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Inmunidad Adaptativa , Animales , Citocinas/metabolismo , Progresión de la Enfermedad , Fibrosis , HumanosRESUMEN
Treatment-related side effects are a major clinical problem in cancer treatment. They lead to reduced compliance to therapy as well as increased morbidity and mortality. Well-known are the sequelae of chemotherapy on the heart, especially in childhood cancer survivors. Therefore, measures to mitigate the adverse events of cancer therapy may improve health and quality of life in patients with cancer, both in the short and long term. The renin-angiotensin system (RAS) affects all hallmarks of cancer, and blockage of the RAS is associated with an improved outcome in several cancer types. There is also increasing evidence that inhibition of the RAS might be able to alleviate or even prevent certain types of cancer treatment-related adverse effects. In this review, we summarize the potential of RAS inhibitors to mitigate cancer treatment-related adverse events, with a special emphasis on chemotherapy-induced cardiotoxicity, radiation injury, and arterial hypertension. Clin Cancer Res; 24(16); 3803-12. ©2018 AACR.