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BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.
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AIM: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. METHODS: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. RESULTS: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD. CONCLUSIONS: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.
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BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.
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Fenotipo , Humanos , Femenino , Masculino , Persona de Mediana Edad , Pronóstico , Adulto , Anciano , Cirrosis Hepática/patología , Cirrosis Hepática/diagnóstico , Biopsia , Hígado/patología , Diagnóstico por Imagen de Elasticidad/métodos , Alanina Transaminasa/sangre , Colestasis/patología , Colestasis/diagnósticoRESUMEN
Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16â¯603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10â¯920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.
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Carcinoma Hepatocelular , Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas , Hígado Graso , Neoplasias Hepáticas , Adulto , Humanos , Masculino , Adolescente , Persona de Mediana Edad , Femenino , Diagnóstico por Imagen de Elasticidad/métodos , Estudios de Cohortes , Vibración , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/patología , Hemorragia Gastrointestinal , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Hígado Graso/complicaciones , Hígado Graso/patología , Neoplasias Hepáticas/patologíaRESUMEN
OBJECTIVE: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. DESIGN: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. RESULTS: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). CONCLUSIONS: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.
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Neoplasias Hepáticas , Enfermedades Metabólicas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/patología , Cirrosis Hepática/patología , Fibrosis , Neoplasias Hepáticas/complicaciones , FerritinasRESUMEN
Metabolic-associated steatotic liver disease (MASLD) encompasses a wide spectrum of metabolic conditions associated with an excess of fat accumulation in the liver, ranging from simple hepatic steatosis to cirrhosis and hepatocellular carcinoma. Finding appropriate tools to study its development and progression is essential to address essential unmet therapeutic and staging needs. This review discusses advantages and shortcomings of different dietary, chemical and genetic factors that can be used to mimic this disease and its progression in mice from a hepatic and metabolic point of view. Also, this review will highlight some additional factors and considerations that could have a strong impact on the outcomes of our model to end up providing recommendations and a checklist to facilitate the selection of the appropriate MASLD preclinical model based on clinical aims.
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Carcinoma Hepatocelular , Hígado Graso , Neoplasias Hepáticas , Animales , Ratones , Cirrosis HepáticaRESUMEN
Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
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Cirrosis Hepática , Neuroblastoma , Animales , Humanos , Ratones , Tetracloruro de Carbono/toxicidad , Células Estrelladas Hepáticas/metabolismo , Hígado/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/tratamiento farmacológico , Neuroblastoma/patología , OncogenesRESUMEN
BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.
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Vesículas Extracelulares , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Molécula de Adhesión Celular Epitelial/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Vesículas Extracelulares/metabolismo , Biomarcadores , Modelos Animales de Enfermedad , Dieta Alta en GrasaRESUMEN
BACKGROUND & AIMS: Advanced hepatic fibrosis is the main risk factor of liver-related morbidity and mortality in patients with chronic liver disease. In this study, we assessed the potential role of bone morphogenetic protein 8A (BMP8A) as a novel target involved in liver fibrosis progression. METHODS: Histological assessment and BMP8A expression were determined in different murine models of hepatic fibrosis. Furthermore, serum BMP8A was measured in mice with bile duct ligation (BDL), in 36 subjects with histologically normal liver (NL) and in 85 patients with biopsy-proven non-alcoholic steatohepatitis (NASH): 52 with non- or mild fibrosis (F0-F2) and 33 with advanced fibrosis (F3-F4). BMP8A expression and secretion was also determined in cultured human hepatocyte-derived (Huh7) and human hepatic stellate (LX2) cells stimulated with transforming growth factor êµ (TGFêµ). RESULTS: Bmp8a mRNA levels were significantly upregulated in livers from fibrotic mice compared to control animals. Notably, serum BMP8A levels were also elevated in BDL mice. In addition, in vitro experiments showed increased expression and secretion to the culture supernatant of BMP8A in both Huh7 and LX2 cells treated with TGFêµ. Noteworthy, we found that serum BMP8A levels were significantly higher in NASH patients with advanced fibrosis than in those with non- or mild fibrosis. In fact, the AUROC of circulating BMP8A concentrations to identify patients with advanced fibrosis (F3-F4) was 0.74 (pË0.0001). Moreover, we developed an algorithm based on serum BMP8A levels that showed an AUROC of 0.818 (pË0.0001) to predict advanced fibrosis in NASH patients. CONCLUSION: This study provides experimental and clinical evidence indicating that BMP8A is a novel molecular target linked to liver fibrosis and introduces an efficient algorithm based on serum BMP8A levels to screen patients at risk for advanced hepatic fibrosis.
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A common splice variant in HSD17B13 (rs72613567:TA) was recently found to be associated with a reduced risk of developing chronic liver disease in NAFLD patients and a reduced risk of progression to advanced fibrosis and cirrhosis. In this study, we aimed to evaluate the prognosis of cirrhotic patients harboring this variant. We performed a retrospective analysis on 483 prospectively recruited patients from four different hospitals in Spain, followed-up for at least 5 years. We collected clinical, demographic, and biochemical data, and we performed a genotyping analysis for common variants previously associated with liver disease risk (HSD17B13 rs72613567:TA and PNPLA3 rs738409). Patients homozygous for the TA allele showed a higher MELD score (p = 0.047), Child−Turcotte−Pugh score (p = 0.014), and INR levels (p = 0.046), as well as decreased albumin (p = 0.004) at baseline. After multivariate analysis, patients with the "protective" variant indeed had an increased risk of hepatic decompensation [aHR 2.37 (1.09−5.06); p = 0.029] and liver-related mortality [aHR 2.32 (1.20−4.46); p = 0.012]. Specifically, these patients had an increased risk of developing ascites (Log-R 11.6; p < 0.001), hepatic encephalopathy (Log-R 10.2; p < 0.01), and higher mortality (Log-R 14.1; p < 0.001) at 5 years of follow-up. Interactions with the etiology of the cirrhosis and with the variant rs738409 in PNPLA3 are also described. These findings suggest that the variant rs72613567:TA in HSD17B13 has no protective effect, but indeed increases the risk of decompensation and death in patients with advanced chronic liver disease.
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17-Hidroxiesteroide Deshidrogenasas , Enfermedad del Hígado Graso no Alcohólico , Polimorfismo de Nucleótido Simple , 17-Hidroxiesteroide Deshidrogenasas/genética , Albúminas , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/mortalidad , Mutación con Pérdida de Función , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/mortalidad , Estudios RetrospectivosRESUMEN
Tissue-to-tissue crosstalk regulates organ function, according to growing data. This phenomenon is relevant for pancreatic ß-cells and the liver, as both tissues are involved in glucose homeostasis and lipid metabolism. The ability to fine-tune regulation and adaptive responses is enabled through communication between pancreatic ß-cells and the liver. However, the crosstalk between both tissues changes when metabolic dysregulation is present. Factors and cargo from extracellular vesicles (EVs) released by liver and pancreatic ß-cells that reach the circulation form the words of this interaction. The molecules released by the liver are called hepatokines and are usually secreted in response to the metabolic state. When hepatokines reach the pancreatic islets several mechanisms are initiated for their protection or damage. In the case of the crosstalk between pancreatic ß-cells and the liver, only one factor has been found to date. This protein, pancreatic derived factor (PANDER) has been proposed as a novel linker between insulin resistance (IR) and type 2 diabetes mellitus (T2D) and could be considered a biomarker for non-alcoholic fatty liver disease (NAFLD) and T2D. Furthermore, the cargo released by EVs, mainly miRNAs, plays a significant role in this crosstalk. A better knowledge of the crosstalk between liver and pancreatic ß-cells is essential to understand both diseases and it could lead to better prevention and new therapeutic options.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Islotes Pancreáticos , Enfermedad del Hígado Graso no Alcohólico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being non-alcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about its involvement in NAFLD onset and progression. This study aimed to elucidate the impact of BMP2 in NAFLD pathophysiology. METHODS: Hepatic and circulating levels of BMP2 were quantified in serum and liver specimens from 115 biopsy-proven NAFLD patients and 75 subjects with histologically normal liver (NL). In addition, BMP2 content and release was determined in cultured human hepatocytes upon palmitic acid (PA) overload. RESULTS: We found that BMP2 expression was abnormally increased in livers from NAFLD patients than in subjects with NL and this was reflected in higher serum BMP2 levels. Notably, we observed that PA upregulated BMP2 expression and secretion by human hepatocytes. An algorithm based on serum BMP2 levels and clinically relevant variables to NAFLD showed an AUROC of 0.886 (95%CI, 0.83-0.94) to discriminate NASH. We used this algorithm to develop SAN (Screening Algorithm for NASH): a SAN < 0.2 implied a low risk and a SAN ≥ 0.6 indicated high risk of NASH diagnosis. CONCLUSION: This proof-of-concept study shows BMP2 as a new molecular target linked to NAFLD and introduces SAN as a simple and efficient algorithm to screen individuals at risk for NASH.
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The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Carbamoil-Fosfato Sintasa (Amoniaco)/genética , Carbamoil-Fosfato Sintasa (Amoniaco)/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Humanos , Hígado/metabolismo , Cirrosis Hepática/patología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Urea/metabolismoRESUMEN
BACKGROUND: NAFLD clinical trials have shown suboptimal results, particularly for liver fibrosis, despite the robust preclinical drug development. We aimed to assess the histological response after the experimental treatment versus placebo by carrying out a meta-analysis of NAFLD clinical trials. METHODS: After a systematic review of NAFLD clinical trials to May 2021, applying strict selection criteria, the following primary outcomes were observed: (a) NASH resolution, with no worsening of fibrosis when available; (b) fibrosis improvement ≥ 1 stage, with no worsening of NAS when available; (c) worsening of NAS; (d) worsening of liver fibrosis ≥ 1 stage, including the progression to cirrhosis on histopathology. Other histological, clinical, and biochemical outcomes were considered secondary endpoints. Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. RESULTS: Twenty-seven randomized clinical trials were included. The pooled efficacy for NASH resolution receiving experimental therapy was 19% (95%CI 15-23; I2 96.2%) compared with placebo 10% (95%CI 7-12; I2 85.8%) (OR 1.66 (95%CI 1.24-2.21); I2 57.8%), while it was 26% (95%CI 22-29); I2 90%)) versus 18% (95%CI 15-21; I2 59%)) for fibrosis improvement (OR 1.34 (95%CI 1.13-1.58); I2 25.4%). For these outcomes, the therapy showed higher efficacy in trials longer than 48 weeks, with < 60% of diabetic population, and when it targeted FXR, PPAR, and antidiabetic mechanisms, and with a NAS < 5 for NASH resolution. Also, NASH (OR 0.57 (95%CI 0.39-0.84); I2 67%) and fibrosis worsening (OR 0.65 (95%CI 0.46-0.92); I2 61.9%) were prevented with the therapy. CONCLUSION: This meta-analysis provides information about the efficacy of the therapy versus placebo by comparing different and combined trial outcomes such as NASH resolution, fibrosis improvement, and NAS and fibrosis worsening. Changes in the experimental design and selection criteria of the clinical trials might be suitable to increase the efficacy.
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Enfermedad del Hígado Graso no Alcohólico , Biopsia , Humanos , Hipoglucemiantes/uso terapéutico , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. METHODS: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+ CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. RESULTS: EpCAM+ CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). CONCLUSION: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.