New advances of artificial intelligence in the diagnosis of non-alcoholic fatty liver disease / 中华肝脏病杂志

Artificial intelligence (AI) refers to the use of computer programs to simulate and extend human intelligence, and has application prospects in the diagnosis and treatment of diseases. This review focuses on the research status of the screening and diagnosis of NAFLD and nonalcoholic steatohepatitis using artificial intelligence technology, electronic health record data, multi-omics prediction models, image recognition technology based on liver imaging and pathological biopsy, and new drugs research and development, with a view to provide new ideas for the diagnosis and treatment.

Liver fibrosis inhibits lethal injury through D-galactosamine/lipopolysaccharide-induced necroptosis / 中华肝脏病杂志

Objective: To explore the new mechanism of liver fibrosis through D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced necroptosis as an entry point to inhibit lethal injury. Methods: The carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was established. At 6 weeks of fibrosis, the mice were challenged with a lethal dose of D-GalN/LPS, and the normal mice treated with the same treatment were used as the control. The experiment was divided into four groups: control group (Control), acute injury group (D-GalN/LPS), liver fibrosis group (Fib), and liver fibrosis + acute challenge group (Fib + D-GalN/LPS). Quantitative PCR and immunofluorescence were used to analyze the expression of necroptosis key signal molecules RIPK1, RIPK3, MLKL and/or P-MLKL in each group. Normal mice were treated with inhibitors targeting key signaling molecules of necroptosis, and then given an acute challenge. The inhibitory effect of D-GalN/LPS-induced-necroptosis on acute liver injury was evaluated according to the changes in transaminase levels and liver histology. Liver fibrosis spontaneous ablation model was established, and then acute challenge was given. Necroptosis key signal molecules expression was analyzed in liver tissue of mice in each group and compared by immunohistochemistry. The differences between groups were compared with t-test or analysis of variance. Results: Quantitative PCR and immunofluorescence assays result showed that D-GalN/LPS-induced significant upregulation of RIPK1, RIPK3, MLKL and/or P-MLKL. Necroptosis key signal molecules inhibition had significantly reduced D-GalN/LPS-induced liver injury, as manifested by markedly reduced serum ALT and AST levels with improvement in liver histology. Necroptosis signaling molecules expression was significantly inhibited in fibrotic livers even under acute challenge conditions. Additionally, liver fibrosis with gradual attenuation of fibrotic ablation had inhibited D-GalN/LPS-induced necroptosis. Conclusion: Liver fibrosis may protect mice from acute lethal challenge injury by inhibiting D-GalN/LPS-induced necroptosis.

Study on the diagnostic value of transient elastography, APRI and FIB-4 for liver fibrosis in children with non-alcoholic fatty liver disease / 中华肝脏病杂志

Objective: To evaluate the diagnostic value of transient elastography, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on 4 factors (FIB-4) for liver fibrosis in children with non-alcoholic fatty liver disease (NAFLD). Methods: A retrospective study was conducted on 100 cases of nonalcoholic fatty liver disease in Hunan Children's Hospital between August 2015 to October 2020 to collect liver tissue pathological and clinical data. The receiver operating characteristic curve (ROC curve) was used to analyze the diagnostic value of liver stiffness measurement (LSM), APRI and FIB-4 in the diagnosis of different stages of liver fibrosis caused by NAFLD in children. Results: The area under the ROC curve (AUC) value of LSM, APRI and FIB-4 for diagnosing liver fibrosis (S≥1) were 0.701 [95% confidence interval (CI): 0.579 ~ 0.822, P = 0.011], 0.606 (95%CI: 0.436 ~ 0.775, P = 0.182), and 0.568 (95%CI: 0.397 ~ 0.740, P = 0.387), respectively. The best cut-off values were 6.65 kPa, 21.20, and 0.18, respectively. The AUCs value of LSM, APRI, and FIB-4 for diagnosing significant liver fibrosis (S≥ 2) were 0.660 (95% CI: 0.552 ~ 0.768, P = 0.006), 0.578 (95% CI: 0.464 ~ 0.691, P = 0.182) and 0.541 (95% CI: 0.427 ~ 0.655, P = 0.482), respectively. The best cut-off values were 7.35kpa, 24.78 and 0.22, respectively. The AUCs value of LSM, APRI and FIB-4 for the diagnosis of advanced liver fibrosis (S≥ 3) were 0.639 (95% CI: 0.446 ~ 0.832, P = 0.134), 0.613 (95% CI: 0.447 ~ 0.779, P = 0.223) and 0.587 (95% CI: 0.411 ~ 0.764, P = 0.346), respectively. The best cut-off values were 8.55kpa, 26.66 and 0.27, respectively. Conclusion: The transient elastography technique has a better diagnostic value than APRI and FIB-4 for liver fibrosis in children with NAFLD.

Ethyl Acetate Fraction of Dicliptera chinensis (L.) Juss. Ameliorates Liver Fibrosis by Inducing Autophagy via PI3K/AKT/mTOR/p70S6K Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate the molecular mechanism underlying the anti-hepatic fibrosis activity of ethyl acetate fraction Dicliptera chinensis (L.) Juss. (EDC) in human hepatic stellate cells (HSCs) in vitro and in a carbon tetrachloride (CCl4)-induced hepatic fibrosis mouse model in vivo.@*METHODS@#For in vitro study, HSCs were pre-treated with platelet-derived growth factor (10 ng/mL) for 2 h to ensure activation and treated with EDC for 24 h and 48 h, respectively. The effect of EDC on HSCs was assessed using cell counting kit-8 assay, EdU staining, transmission electron microscopy, immunofluorescence staining, and Western blot, respectively. For in vivo experiments, mice were intraperitoneally injected with CCl4 (2 ° L/g, adjusted to a 25% concentration in olive oil), 3 times per week for 6 weeks, to develop a hepatic fibrosis model. Forty 8-week-old male C57BL/6 mice were divided into 4 groups using a random number table (n=10), including control, model, positive control and EDC treatment groups. Mice in the EDC and colchicine groups were intragastrically administered EDC (0.5 g/kg) or colchicine (0.2 mg/kg) once per day for 6 weeks. Mice in the control and model groups received an equal volume of saline. Biochemical assays and histological examinations were used to assess liver damage. Protein expression levels of α -smooth muscle actin (α -SMA) and microtubule-associated protein light chain 3B (LC3B) were measured by Western blot.@*RESULTS@#EDC reduced pathological damage associated with liver fibrosis, downregulated the expression of α -SMA and upregulated the expression of LC3B (P<0.05), both in HSCs and the CCl4-induced liver fibrosis mouse model. The intervention of bafilomycin A1 and rapamycin in HSCs strongly supported the notion that inhibition of autophagy enhanced α -SMA protein expression levels (P<0.01). The results also found that the levels of phosphoinositide (PI3K), p-PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, and p-p70S6K all decreased after EDC treatment (P<0.05).@*CONCLUSIONS@#EDC has anti-hepatic fibrosis activity by inducing autophagy and might be a potential drug to be further developed for human liver fibrosis therapy.

Geniposide inhibits hepatic fibrosis and hepatic stellate cell activation through blocking the TGF-β1/Smad signaling pathway / 生理学报

The purpose of this study was to investigate the effect of Geniposide on hepatic fibrosis and activation of hepatic stellate cells (HSCs) and to explore possible underlying mechanism. Human HSCs (LX-2) were treated with 5 ng/mL transforming growth factor-β1 (TGF-β1), followed by co-culture with Geniposide at various concentrations (0, 1, 2.5, 5, 10, 20, 40, 60, 80, 100 μmol/L). Cell viability was determined by MTT assay. Then, LX-2 cells were divided into control, TGF-β1 (5 ng/mL) and TGF-β1 + Geniposide (20 μmol/L) groups, and the gene and protein expression of collagen I, fibronectin, α-smooth muscle actin (α-SMA), p-Smad2 and p-Smad3 was detected by qPCR and Western blot, respectively. BALB/c mice were treated with CCl4 (25%, 1 mL/kg) to generate a model of hepatic fibrosis (CCl4 group), and the control group and CCl4 + Geniposide group were administered with olive oil and CCl4 + 40 mg/kg Geniposide, respectively. After 4 weeks of treatment, the liver function and serum hepatic fibrosis indexes of mice were detected, histological observation was performed by HE and Masson staining, and α-SMA expression in the tissue was analyzed by immunohistochemistry. Western blot was utilized for the determination of the protein expression of α-SMA, TGF-β1, p-Smad2 and p-Smad3. The results showed that Geniposide inhibited LX-2 cell proliferation. In addition, Geniposide significantly downregulated the gene and protein expression of collagen I, fibronectin and α-SMA and the expression of TGF-β1/Smad signaling-related proteins induced by TGF-β1 in vitro. Histological observations showed that Geniposide significantly inhibited CCl4-induced hepatic fibrosis, HSC activation and expression of TGF-β1/Smad signaling-related proteins in mice. In summary, Geniposide prevents the hepatic fibrosis and HSC activation possibly through the inhibition of the TGF-β1/Smad signaling pathway.

Non-invasive tests of non-alcoholic fatty liver disease / 中华医学杂志(英文版)

For the detection of steatosis, quantitative ultrasound imaging techniques have achieved great progress in past years. Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis. Some blood biomarkers correlate with non-alcoholic steatohepatitis, but the accuracy is modest. Regarding liver fibrosis, liver stiffness measurement by transient elastography (TE) has high accuracy and is widely used across the world. Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability. Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response. This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease (NAFLD). Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict the prognosis. Further studies are needed to determine the role of the tests as monitoring tools. We cannot overemphasize the importance of context in selecting appropriate tests.

Acoustic radiation force impulse elastography and liver fibrosis risk scores in severe obesity

ABSTRACT Objective: Identifying significant fibrosis is crucial to evaluate the prognosis and therapeutic interventions in patients with nonalcoholic fatty liver disease (NAFLD). We assessed the performance of acoustic radiation force impulse (ARFI) elastography, APRI, FIB-4, Forns, NFS and BARD scores in determining liver fibrosis in severe obesity. Subjects and methods: A prospective study included 108 patients undergoing bariatric surgery. Liver biopsy specimens were obtained intraoperatively and classified according to the NAFLD Activity Score. Patients were assessed with serological markers and shear wave velocity of the liver was measured with the Siemens S2000 ultrasound system preoperatively. Optimal cut-off values were determined using the area under the receiver operating characteristic curves (AUROC). Results: In the entire cohort prevalence of NAFLD was 80.6%, steatohepatitis 25.9% and significant fibrosis 19.4%. The best tests for predicting significant fibrosis were FIB-4 and Forns scores (both AUROC 0.78), followed by APRI (AUROC 0.74), NFS (AUROC 0.68), BARD (AUROC 0.64) and ARFI (AUROC 0.62). ARFI elastography was successful in 73% of the patients. Higher body mass index (BMI) correlated with invalid ARFI measurements. In patients with BMI < 42 kg/m2, ARFI showed 92.3% sensitivity and 82,6% specificity for the presence of significant fibrosis, with AUROC 0.86 and cut-off 1.32 m/s. Conclusions: FIB-4 and Forns scores were the most accurate for the prediction of significant fibrosis in bariatric patients. Applicability and accuracy of ARFI was limited in individuals with severe obesity. In patients with BMI < 42 kg/m2, ARFI elastography was capable for predicting significant fibrosis with relevant accuracy.

Correlation between COVID-19 severity, body mass index and radiological hepatic morphology / Correlación entre la gravedad de COVID-19, el índice de masa corporal y la morfología hepática radiológica

SUMMARY: Obesity and fatty liver steatosis are already considered metabolic risk factors which may aggravate the severity of COVID-19. This study aims to investigate the correlation between COVID-19 severity, obesity, and liver steatosis and fibrosis. 230 consecutive patients with laboratory-confirmed COVID-19 aged between 15 and 84? years, admitted to a hospital devoted to COVID-19 patients, were enrolled in the study. COVID-19 severity was classified as severe versus non-severe based on admission to ICU. Obesity was assessed by Body Mass Index (BMI). CT-scan was used to check for the liver steatosis. Fibrosis-4 score was calculated. The study was conducted in March-May 2020. Obesity strongly and positively correlated with severe COVID-19 illness r: 0.760 (P<0.001). Hepatic steatosis had rather less of a correlation with COVID-19 severity r: 0.365 (P<0.001). Multivariable-adjusted association between hepatic steatosis or obesity, or both (as exposure) and COVID-19 severity (as the outcome) revealed increased risk of severe COVID-19 illness with obesity (Adjusted model I OR: 465.3, 95 % CI: 21.9-9873.3, P<0.001), with hepatic steatosis (Adjusted model I OR: 5.1, 95 % CI: 1.2-21.0, P<0.025), and with hepatic steatosis among obese patients (Adjusted model I OR: 132, 95 % CI: 10.3-1691.8, P<0.001). Obesity remained the most noticeable factor that strongly correlated with COVID-19 severity, more than liver steatosis. However, the risk to COVID-19 severity was greater in those with both factors: obesity and liver steatosis.

RESUMEN: La obesidad y la esteatosis del hígado graso ya se consideran factores de riesgo metabólico que pueden empeorar la gravedad de la COVID-19. Este estudio tiene como objetivo investigar la correlación entre la gravedad de COVID- 19, la obesidad y la esteatosis y fibrosis hepática. El estudio se realizó en 230 pacientes consecutivos entre 15 y 84 años con COVID-19 confirmado por laboratorio, ingresados en un hospital dedicado a pacientes con COVID-19. La gravedad de COVID-19 se clasificó como grave, versus no grave según el ingreso a la UCI. La obesidad se evaluó mediante el índice de masa corporal (IMC). Se utilizó una tomografía computarizada para verificar la esteatosis hepática. Se calculó la puntuación de Fibrosis-4. El estudio se realizó entre marzo-mayo de 2020. La obesidad se correlacionó fuerte y positivamente con la enfermedad grave de COVID-19 r: 0,760 (P <0,001). La esteatosis hepática tuvo una correlación bastante menor con la gravedad de COVID-19 r: 0.365 (P <0.001). La asociación ajustada multivariable entre la esteatosis hepática u obesidad, o ambas (como exposición) y la gravedad de COVID-19 (como resul- tado) reveló un mayor riesgo de enfermedad grave por COVID- 19 con obesidad (OR del modelo ajustado I: 465,3, IC del 95%: 21,9 -9873,3, P <0,001), con esteatosis hepática (OR del modelo I ajustado: 5,1, IC del 95 %: 1,2-21,0, P <0,025) y con esteatosis hepática entre los pacientes obesos (OR del modelo I ajustado: 132, IC del 95 % : 10,3-1691,8, P <0,001). La obesidad siguió siendo el factor más notable que se correlacionó significativamente con la gravedad de COVID-19, más que la esteatosis hepática. Sin embargo, el riesgo de gravedad de COVID-19 fue mayor en aquellos con ambos factores: la obesidad y esteatosis hepática.

Gamma-glutamyl transpeptidase-platelet ratio, systemic immune inflammation index, and system inflammation response index in invasive Aspergillosis

SUMMARY OBJECTIVE: Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index are three systemic immune and inflammation indexes that were investigated for their diagnostic and prognostic proficiencies in cardiovascular diseases and cancers. However, their predictive values for invasive aspergillosis have not yet been studied. The aim of this study was to evaluate Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index levels and their diagnostic values in invasive aspergillosis. METHODS: A total of 23 patients with invasive aspergillosis and 23 sex- and age-matched healthy participants were included in this study. Complete blood count parameters and liver function tests were studied. Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index were calculated. RESULTS: Leukocyte, neutrophil, lymphocyte, and monocyte levels were statistically significantly higher in IA group (p=0.031, p=0.027, p=0.033, and p=0.001, respectively). In invasive aspergillosis group, platelets were numerically lower; Aspartate transaminase, alanine aminotransferase, and lactic dehydrogenase levels were numerically higher than those in control group but differences between levels were not statistically significant (p>0.05). The γ-glutamyl transpeptidase levels of patients were statistically significantly higher (p=0.007), and in addition, statistically significant differences were found between groups in terms of gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index (p<0.001, p=0.037, p=0.001, respectively). Receiver operating characteristic analysis was performed, and areas under the curves were evaluated. gamma-glutamyl transpeptidase-platelet ratio had the higher area under the curve than systemic immune inflammation index and system inflammation response index (AUC 0.849, 0.798, 0.693, respectively). The results from receiver operating characteristic analysis of the data suggested that the use of a cutoff value of 0.15 for gamma-glutamyl transpeptidase-platelet ratio would be optimum for clinical use to confirm independent predictors of patients with invasive aspergillosis. CONCLUSIONS: Gamma-glutamyl transpeptidase-platelet ratio is an independent, a useful predictor, and is superior to other evaluated markers in the diagnosis of inflammation in invasive aspergillosis. Gamma-glutamyl transpeptidase-platelet ratio may also be a helpful biomarker for clinicians to follow-up the inflammatory process of these patients.

Liver structural injury in leptin-deficient (ob/ob) mice: lipogenesis, fibrogenesis, inflammation, and apoptosis / Lesión estructural del hígado en ratones con deficiencia de leptina (ob/ob): lipogénesis, fibrogénesis, inflamación y apoptosis

SUMMARY: Nonalcoholic fatty liver disease (NAFLD) might progress the steatosis to nonalcoholic steatohepatitis (NASH), reaching a cirrhosis state and possibly hepatocellular carcinoma. The liver of three-month-old C57BL/6J mice (wild-type, WT group, n=10) and leptin- deficient obese mice (ob/ob group, n=10) were studied, focusing on the mechanisms associated with the activation of the hepatic stellate cells (HSCs) and pro-fibrogenesis. The obese ob/ob animals' liver showed steatosis, increased lipogenesis gene expressions, inflammation, increased pro-inflammatory gene expressions, inflammatory infiltrate, and potential apoptosis linked to a high Caspase 3 expression. In ob/ob mice, liver sections were labeled in the fibrotic zones by anti-alpha-smooth muscle actin (alpha-SMA) and anti-Reelin, but not in the WT mice. Moreover, the alpha-SMA gene expression was higher in the ob/ob group's liver than the WT group. The pro-fibrogenic gene expressions were parallel to anti- alpha-SMA and anti-Reelin immunofluorescence, suggesting HSCs activation. In the ob/ob animals, there were increased gene expressions involved with lipogenesis (Peroxisome proliferator-activated receptor-gamma, Cell death-inducing DFFA-like effector-c, Sterol regulatory element-binding protein-1c, and Fatty acid synthase), pro-fibrogenesis (Transforming growth factor beta1, Smad proteins- 3, Yes-associated protein-1, Protein platelet-derived growth factor receptor beta), pro-inflammation (Tumor necrosis factor-alpha, and Interleukin-6), and apoptosis (Caspase 3). In conclusion, the results in obese ob/ob animals provide a clue to the events in humans. In a translational view, controlling these targets can help mitigate the hepatic effects of human obesity and NAFLD progression to NASH.

RESUMEN: La enfermedad del hígado graso no alcohólico (HGNA) puede progresar de la esteatosis a esteatohepatitis no alcohólica (ENA), alcanzando un estado de cirrosis y posiblemente carcinoma hepatocelular. Se estudió el hígado de ratones C57BL / 6J de tres meses de edad (tipo salvaje, grupo WT, n = 10) y ratones obesos con deficiencia de leptina (grupo ob/ob, n = 10), centrándose en los mecanismos asociados con la activación de las células estrelladas hepáticas (HSC) y profibrogénesis. El hígado de los animales obesos ob/ob mostró esteatosis, aumento de la expresión génica de la lipogénesis, inflamación, aumento de la expresión génica proinflamatoria, infiltrado inflamatorio y posible apoptosis ligada a una alta expresión de Caspasa 3. En ratones ob/ob, las sec- ciones de hígado se marcaron en las zonas fibróticas con anti-alfa- actina de músculo liso (alfa-SMA) y anti-Reelin, pero no en los ratones WT. Además, la expresión del gen alfa-SMA fue mayor en el hígado del grupo ob/ob que en el grupo WT. Las expresiones génicas profibrogénicas fueron paralelas a la inmunofluorescencia anti-alfa-SMA y anti-Reelin, lo que sugiere la activación de las HSC. En los animales ob/ob, hubo un aumento de las expresiones génicas involucradas con la lipogénesis (receptor activado por proliferador de peroxisoma gamma, efector c similar a DFFA inductor de muerte celular, proteína de unión al elemento regulador de esterol-1c y sintasa de ácidos grasos), pro-fibrogénesis (factor de crecimiento transformante beta 1, proteínas Smad-3, proteína-1 asociada a Yes, receptor beta del factor de crecimiento derivado de plaquetas de proteínas), proinflamación (factor de necrosis tumoral alfa e interleucina-6) y apoptosis (caspasa 3). ). En conclusión, los resultados en animales obesos ob/ob proporcionan una pista de los eventos en humanos. Desde un punto de vista traslacional, el control de estos objetivos puede ayudar a mitigar los efectos hepáticos de la obesidad humana y la progresión de HGNA a ENA.

Avaliação do desempenho do índice triglicerídeo-glicose no diagnóstico e estadiamento da DHGNA em pacientes obesos / Performace of triglyceride-glucose index on diagnosis and staging of nafld in obese patients

ABSTRACT BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the world, and its prevalence is increasing alongside obesity. In United States, NAFLD is already the second leading cause of liver transplantation. The spectrum of the disease ranges from simple steatosis, which has a benign course, to steatohepatitis, which may progress to cirrhosis and its complications. The rising of noninvasive methods for diagnosing and staging non-alcoholic steatohepatitis (NASH) and fibrosis decreases the need of liver biopsy, as well as the costs and the occurrence of complications related to it. OBJECTIVE: To analyze the performance of the triglyceride-glucose index to evaluate steatosis, NASH and liver fibrosis in obese patients with NAFLD. METHODS: This is a retrospective cross-sectional study. Every medical record of patients who were candidates for bariatric surgery at a leading hospital in Southern Brazil were analyzed. The triglyceride-glucose index (TyG Index), a method composed only of two simple laboratory tests (serum triglycerides and fasting glucose levels), was performed prior to surgery. The TyG Index performance regarding the anatomopathological findings was evaluated, and the AUROC curve was calculated to evaluate the best cut-off point for diagnosing steatosis, non-alcoholic steatohepatitis and liver fibrosis grade. Also, the NAFLD fibrosis Score (NFS) was evaluated. RESULTS: A total of 423 patients were evaluated. The TyG Index with a cut-off point of 8.76 excluded significant simple steatosis (grade 2-3) in obese patients, with 67.6% sensitivity, 65.1% specificity, 46.3% positive predictive value (PPV), 81.8% negative predictive value (NPV), 65.8% accuracy and 0.66 AUROC (P=0.005). In the evaluation of NASH, the TyG Index with a cut-off point of 8.82 excluded significant NASH (grade 2-3) with 57.3% sensitivity, 58.6% specificity, 33.7% PPV, 78.8% NPV, 58.2% accuracy and 0.58 AUROC (P=0.022). When evaluating liver fibrosis, the TyG Index with a cut-off point of 8.91 showed a sensitivity of 61.8%, a specificity of 62.5%, a PPV of 13.8 and a NPV of 94.4% for exclusion of advanced fibrosis (F3-4), with a 62.4% accuracy and 0.69 AUROC (P<0.001). When analyzing the performance of NFS in the diagnosis of advanced fibrosis, the cut-off point <-1.455 excluded advanced fibrosis with sensitivity of 59.4%, specificity of 51%, PPV of 11%, NPV of 92.4% and accuracy of 51.7%. However, the cut-off point of 0.676 to diagnose advanced fibrosis presented sensitivity of 21.9%, specificity of 83%, PPV of 11.7%, NPV of 91.2% and 77.3% accuracy. The AUROC was 0.54 (P=0.480). CONCLUSION: TyG Index did not perform well in the diagnosis of significant steatosis and NASH. However, it was able to exclude advanced fibrosis in obese patients who are candidates for bariatric surgery.

RESUMO CONTEXTO: A doença hepática gordurosa não-alcoólica (DHGNA) é a doença hepática mais prevalente no mundo. Nos Estados Unidos, a DHGNA já é a segunda causa de transplante hepático. O espectro da doença abrange desde a esteatose simples, que apresenta curso benigno, até esteato-hepatite não-alcoólica (EHNA), que pode progredir para cirrose e suas complicações. O desenvolvimento de métodos não invasivos para o diagnóstico e estadiamento da EHNA e da fibrose hepática visa diminuir a necessidade de biópsia hepática, um procedimento invasivo e não raro associado a complicações. OBJETIVO: Analisar o desempenho do índice triglicerídeo-glicose (TyG Index) para o diagnóstico e estadiamento da DHGNA em pacientes obesos. MÉTODOS: Este é um estudo transversal retrospectivo. Foram analisados todos os prontuários de pacientes candidatos a cirurgia bariátrica em um hospital de referência do Sul do Brasil e calculado o TyG Index, um escore composto por dois exames laboratoriais (triglicerídeos e glicose de jejum), realizados previamente à cirurgia. O desempenho do TyG Index em relação aos achados anatomopatológicos hepáticos foi avaliado, e calculada a curva ROC para avaliação de esteatose simples, EHNA e fibrose hepática. O NAFLD Fibrosis Score (NFS) também foi avaliado. RESULTADOS: Foram avaliados 423 pacientes. O melhor ponto de corte do TyG Index para a exclusão de esteatose simples significativa (grau 2-3) foi de 8,76, com sensibilidade 67,6%, especificidade 65,1%, valor preditivo positivo (VPP) 46,3%, valor preditivo negativo (VPN) 81,8%, acurácia 65,8% e AUROC 0,66 (P=0,005). Na avaliação de EHNA significativa (grau 2-3), o melhor ponto de corte foi de 8,82 com sensibilidade 57,3%, especificidade 58,6%, VPP 33,7%, VPN 78,8%, acurácia 58,8% e AUROC 0,58 (P=0,022). Em relação à fibrose avançada (grau 3-4), o melhor ponto de corte do TyG Index foi de 8,91 com sensibilidade 61,8%, especificidade 62,5%, VPP 13,8%, VPN 94,4%, acurácia 62,4% e AUROC 0,69 (P<0,001). Ao analisarmos o desempenho do NFS no diagnóstico de fibrose avançada, o ponto de corte de <-1,455 excluiu fibrose avançada com sensibilidade 59,4%, especificidade 51%, VPP 11%, VPN 92,4% e acurácia 51,7%. Entretanto, o ponto de corte de 0,676 para fibrose avançada apresentou sensibilidade de 21,9%, especificidade 83%, VPP 11,7%, VPN 91,2% e acurácia 77,3%. A AUROC foi de 0,54 (P=0,480). CONCLUSÃO: O TyG Index não apresentou bom desempenho para o diagnóstico e estadiamento da esteatose simples e da EHNA. Entretanto, foi capaz de excluir fibrose avançada em pacientes obesos candidatos a cirurgia bariátrica.

Razão neutrófilo-linfócito prediz mortalidade em curto prazo em pacientes hospitalizados com cirrose hepática descompensada / Neutrophil-lymphocyte ratio predicts short-term mortality in patients hospitalized for acute decompensation of cirrhosis

ABSTRACT BACKGROUND: Individuals with cirrhosis have a chronic systemic inflammation associated with an immune dysfunction, affecting the progression of the liver disease. The neutrophil-lymphocyte ratio (NLR) was proposed as a marker of systemic inflammatory response and survival in patients with cirrhosis. OBJECTIVE: Evaluate the prognostic role of NLR in cirrhotic patients and its relation with inflammatory cytokines(IL-6, IL-10 and IL-17). METHODS: In this prospective study two groups were evaluated: 1) Stable cirrhotic in outpatient follow-up (n=193); 2) Hospitalized cirrhotic for acute decompensation for at least 48 hours (n=334) with admission and 48 hours tests evaluation. Circulating inflammatory cytokines were available for 130 hospitalized patients. RESULTS: In outpatients with stable cirrhosis, NLR correlated with MELD score and other variables associated with severity of disease. However, after a median of 32 months of follow up NLR was not associated with mortality (HR 1.058, 95%CI 0.900-1.243; P=0.495). In hospitalized patients, NLR at 48-hour after admission was independently associated with 90-day survival (HR 1.061, 95%CI 1.020-1.103; P=0.003) in multivariate Cox-regression analysis. The 90-day Kaplan-Meier survival probability was 87% for patients with a 48-hour NLR <3.6 and 62% for NLR ≥3.6 (P<0.001). Elevation of NLR in the first 48 hours was also independently associated with mortality (HR 2.038, 95%CI 1295-3207; P=0.002). The 90-day Kaplan-Meier survival probability was 83% when NLR did not increase and 62% when NLR increased (P<0.001). IL-6, IL-10 and IL-17 at admission were positively correlated with both admission and 48-hour NLR. Lower levels of baseline IL-10 were associated with NLR increase during first 48-hour. CONCLUSION: NLR evaluated at 48 hours of hospitalization and its early increase after admission were independently associated with short-term mortality in patients hospitalized for acute decompensation of cirrhosis.

RESUMO CONTEXTO: Na cirrose há um quadro crônico de inflamação sistêmica associada a disfunção imune, que impactam na progressão da doença hepática. A razão neutrófilo-linfócito (RNL) foi proposta como um marcador de resposta inflamatória sistêmica e sobrevida em pacientes com cirrose hepática. OBJETIVO: Avaliar o papel de RNL como marcador prognóstico em portadores de cirrose hepática e sua relação com citocinas inflamatórias (IL-6, IL-10 e IL-17). MÉTODOS: É um estudo prospectivo com duas coortes: 1) pacientes cirróticos estáveis em acompanhamento ambulatorial (n=193); 2) pacientes cirróticos hospitalizados por descompensação aguda por no mínimo 48 horas (n=334) com avaliação de exames de admissão de 48 horas. Citocinas inflamatórias séricas estavam disponíveis em 130 pacientes hospitalizados. RESULTADOS: Nos pacientes ambulatoriais com cirrose estável, RNL se correlacionou com MELD e outras variáveis associadas com gravidade da doença. Entretanto, após uma mediana de 32 meses de seguimento, RNL não apresentou associação com mortalidade (HR 1.058, 95%CI 0.900-1.243; P=0.495). Nos pacientes hospitalizados, RNL de 48 horas após a admissão apresentou associação independente com sobrevida em 90 dias (HR 1.061, 95%CI 1.020-1.103; P=0.003) na regressão multivariada de Cox. A probabilidade de sobrevivência pela curva de Kaplan-Meier em 90 dias foi de 87% em pacientes com RNL de 48 horas <3.6 e 62% nos pacientes com RNL ≥3.6 (P<0.001). A elevação de RNL nas primeiras 48 horas também foi um fator independente associado a mortalidade (HR 2.038, 95%CI 1295-3207; P=0.002). A avaliação de sobrevida em 90 dias pela curva de Kaplan-Meier foi de 83% nos pacientes em que RNL não apresentou elevação e 62% nos que apresentaram elevação de RNL (P<0.001). IL-6, IL-10 e IL-17 na admissão se correlacionaram positivamente com RNL de admissão e de 48 horas. Níveis mais baixos de IL-10 basal foram associados com elevação de RNL nas primeiras 48 horas. CONCLUSÃO: RNL avaliada em 48 horas de hospitalização e sua elevação precoce após a admissão foram fatores independentemente associados a mortalidade em curto prazo nos pacientes hospitalizados com descompensação aguda da cirrose.

Regulatory effects of microRNAs on hepatic stellate cell activation and liver fibrogenesis / 中华肝脏病杂志

Hepatic fibrogenesis (HF) is the common consequence of various chronic liver diseases (CLD) induced by a variety of pathogenic factors. The mechanism of HF involves the interactions within different types of liver cells, cytokines, chemokines, cell mediators and multiple signaling pathways in a way of networks. As a result, excessive production and deposition of extracellular matrix (ECM) mainly composed of type I and type III fibril forming collagen destroys the original morphology, structure and function of the liver. The activation of hepatic stellate cells (HSCs), the major scar forming cells in liver, plays a crucial role in hepatic fibrogenesis. MicroRNAs are a group of short, single stranded, non-coding RNAs that can inhibit mRNA expression at the transcriptional and post transcriptional levels. They can be loaded and transferred as cargos by exosomes, to regulate the function of nearby and distant receptive cells. The expressions of many microRNAs such as miR-21, miR-29, miR-708, miR-101, miR-455, miR-146, miR-193 change significantly in activated HSCs, which regulate the activation, fibrogenic function, proliferation, apoptosis and autophagy of HSCs via affecting target genes expression and signaling pathway molecules. They are important substances and regulatory mechanism that mediate the initiation and progression of HF.

Diabetes influences liver stiffness in chronic hepatitis C patients with and without virological cure: A longitudinal study

OBJECTIVES: The aim was to prospectively assess the variation in liver stiffness (LS) and the associated factors for LS progression in a cohort of naïve, non-responder (NR), and sustained virological response (SVR) chronic hepatitis C (CHC) patients. METHODS: This was a longitudinal study on CHC patients prospectively followed with serial elastography (Fibroscan®). The LS progression rate was determined, and the associated factors for progression were assessed using multiple linear regression analysis. RESULTS: A total of 406 patients were followed up for 44 (35-53) months [naïve (29%), NR (24%), and SVR (47%)]. At the end of the follow-up period, the SVR group had a significant decrease in LS [11.8 (9.2) vs. 8.8 (8.4) kPa (p<0.001)], the NR group had a significant increase in LS [6.6 (5.2) vs. 7.1 (4.5) kPa (p=0.069)], and the naïve group had no change in LS [6.3 (3.0) vs. 6.0 (3.8) kPa (p=0.22)]. The related factors for LS progression were lack of SVR (p=0.002) and diabetes (p=0.05). In the non-diabetic SVR group, a negative rate of progression (-0.047 kPa/month) was observed, whereas in the diabetic SVR group, a positive rate of progression (+0.037 kPa/month) was observed. The highest rate of progression was observed in NR with diabetes at the rate of +0.044 kPa/month. CONCLUSION: LS in diabetes patients progresses despite SVR, suggesting the need for a close follow-up of this group post-treatment considering the risk of progression of liver disease even after SVR.

Assessment of liver disease by non-invasive methods in perinatally infected Brazilian adolescents and young adults living with Human Immunodeficiency Virus (HIV)

ABSTRACT Introduction: Effective and long-term combined antiretroviral therapy (cART) has decreased morbidity and mortality in HIV-infected individuals. Despite treatment advances, HIV-infected children continue to develop noninfectious conditions, including liver fibrosis. Methods: Cross-sectional study designed to identify liver fibrosis in HIV-infected adolescents and young adults, in an outpatients clinic of Pediatric Infectious Diseases Division at Escola Paulista de Medicina/Universidade Federal de São Paulo (UNIFESP), diagnosed by noninvasive methods (liver elastography-FibroScan®, APRI and FIB4). Variables examined included demographics, clinical, laboratories, HIV treatment. All participants underwent FibroScan® to measure liver parenchyma elasticity. Values equal to above 7.0 kPa were interpreted as the presence of significant liver fibrosis. Two different biomarkers of liver fibrosis were employed: the AST-to-Platelet Ratio Index (APRI) and the Fibrosis-4 score (FIB-4). APRI values above 1.5 have been considered as levels of clinically significant liver fibrosis and FIB-4 values above 3.25 suggested the presence of advanced fibrosis. Results: Between August 2014 and March 2017, the study enrolled 97 patients, age 10-27 years old, fourteen of 97 subjects (14.4%) presented liver stiffness (≥7 kPa) detected by the liver elastography. No patient had APRI> 1.5. No patient had FIB4 value > 3.25. The only isolated laboratory parameter that could be significantly associated with high liver stiffness was thrombocytopenia (p= 0.022, Fisher's exact test). Conclusion: Liver stiffness was identified in 14.4% (14/97) of this cohort by liver elastography. Liver disease in HIV-infected adolescents and young adults manifests itself silently, so should be routinely investigated.

Is there a link between non-alcoholic fatty liver disease aspects and pancreatic cancer? Results of a case-matched study / Existe ligação entre a doença hepática gordurosa não alcoólica e o câncer de pâncreas? Resultados de estudo caso-controle

ABSTRACT Background and Aims: An association between non-alcoholic fatty liver disease (NAFLD) and pancreatic ductal adenocarcinoma (PDAC) has been previously suggested. This study aims at investigating this association and at identifying potential links between variables of the NAFLD spectrum and PDAC. Methods: A cross-sectional case-matched analytical and comparative study was carried out to analyze patients undergoing surgical resection of PDAC and compare them to a control group of individuals undergoing cholecystectomy at a public tertiary teaching hospital, matched by sex, age and BMI. Hepatic histopathological examinations were compared between cases and controls. Results: Of 56 individuals, 36 were male (64.3%) and the median age was 61.5 years old (interquartile range: 57.5 - 70). The participants' median BMI was 24.3 kg/m2 (interquartile range: 22.1-26.2 kg/m2). Microvesicular steatosis (p=0.04), hepatocellular ballooning (p=0.02), fibrosis (p=0.0003) and steatohepatitis (p=0.03) were significantly more frequent in the group of cases. Odds ratios for hepatocellular ballooning (6.2; 95%CI: 1.2-31.8; p=0.03), fibrosis (9.3; 95%CI: 2.5-34.1; p=0.0008) and steatohepatitis (3.9; 95%CI: 1.1-14.3; p=0.04) were statistically significant in relation to the PDAC prevalence. Conclusions: Significant associations were identified between histopathological aspects of NAFLD (microvesicular steatosis, hepatocellular ballooning, fibrosis, and steatohepatitis) and PDAC.

RESUMO Histórico e objetivos: a associação entre a doença hepática gordurosa não alcoólica (DHGNA) e o adenocarcinoma ductal pancreático (ACDP) foi sugerida anteriormente. Este estudo visa investigar esta associação e identificar possíveis ligações entre as variáveis do espectro da DHGNA e o ACDP. Métodos: foi realizado estudo transversal caso-controle analítico e comparativo para analisar pacientes submetidos a ressecção cirúrgica de ACDP e compará-los a grupo controle de indivíduos submetidos a colecistectomia em hospital público terciário de ensino, pareados por sexo, idade e IMC. Os exames histopatológicos hepáticos foram comparados entre casos e controles. Resultados: dos 56 indivíduos, 36 eram do sexo masculino (64,3%) e a idade mediana era de 61,5 anos de idade (intervalo interquartil 57,5-70). A mediana do IMC dos participantes foi de 24,3 kg/m2 (intervalo interquartil 22,1 26,2). Esteatose microvesicular (p = 0,04), balonização hepatocelular (p = 0,02), fibrose (p = 0,0003) e esteato-hepatite (p = 0,03) foram significativamente mais frequentes no grupo de casos. As razões de chances para balonização hepatocelular (6,2; IC 95%: 1,2 - 31,8; p = 0,03), fibrose (9,3; IC 95%: 2,5 - 34,1; p = 0,0008) e esteato-hepatite (3,9; IC 95%: 1,1 - 14,3; p = 0,04) foram estatisticamente significativas em relação à prevalência de ACDP. Conclusões: houve associações significativas entre aspectos histopatológicos de DHGNA (esteatose microvesicular, balonização hepatocelular, fibrose e esteato-hepatite) e a ocorrência de ACDP.

A review on cell-based models of human liver disease in vitro / 生物医学工程学杂志

Unhealthy diet, habits and drug abuse cause a variety of liver diseases, including steatohepatitis, liver fibrosis, liver cirrhosis and liver cancer, which seriously affect human health. The fabrication of highly simulated cell models in vitro is important in the treatment of liver diseases and drug development. This article summarized the common strategies for the construction of liver pathology models

Blind liver biopsy: a 17-year experience / Biopsia hepática a ciegas: experiencia de 17 años

ABSTRACT Objectives: Liver biopsy is the gold standard for assessing liver inflammation, necrosis and fibrosis. The aim of the study is to evaluate clinical indications and histopathological results of percutaneus liver biopsy. Materials and methods: A total of 516 children who underwent blind liver biopsy were evaluated retrospectively. Results: Blind liver biopsy was performed for chronic active hepatitis B in 50% of the cases (n=260), neonatal cholestasis in 14% (n=68), autoimmune hepatitis in 7.7% (n=40), Wilson disease in 7.3% (n=38), isolated elevation of the liver enzymes in 5% (n=26), chronic active hepatitis C in 4.2% (n=22), metabolic disease in 3.4% (n=17), malignancies in 2.2% (n=11) and the others in 3.4% (n=17). Major complications were observed in 0.19% of the cases (n=1) and minor complications such as pain at the biopsy site in 13.5% of the cases (n=70), hypotension and tachycardia in 1.9% (n=10). Conclusions: Blind liver biopsy is a safe method in diagnosing liver diseases in childhood.

RESUMEN Objetivos: La biopsia de hígado es el estándar de oro para evaluar la inflamación, necrosis y fibrosis del hígado. El objetivo del estudio es evaluar las indicaciones clínicas y los resultados histopatológicos de la biopsia hepática percutánea. Materiales y métodos: Se evaluó retrospectivamente a un total de 516 niños a los que se les realizó una biopsia hepática a ciegas. Resultados: Se realizó biopsia hepática a ciegas por hepatitis B crónica activa en el 50% de los casos (n = 260), colestasis neonatal en el 14% (n = 68), hepatitis autoinmune en el 7,7% (n = 40), enfermedad de Wilson en el 7,3%. % (n = 38), elevación aislada de las enzimas hepáticas en el 5% (n = 26), hepatitis C crónica activa en el 4,2% (n = 22), enfermedad metabólica en el 3,4% (n = 17), neoplasias en el 2,2% (n = 11) y los demás en un 3,4% (n = 17). Se observaron complicaciones mayores en el 0,19% de los casos (n = 1) y complicaciones menores como dolor en el sitio de la biopsia en el 13,5% de los casos (n = 70), hipotensión y taquicardia en el 1,9% (n = 10). Conclusiones: La biopsia hepática a ciegas es un método seguro en el diagnóstico de enfermedades hepáticas en la infancia.

Application of acoustic radiation force impulse elastography combined with serum markers in Child-Pugh grading

OBJECTIVES: Acoustic radiation force impulse (ARFI) elastography, the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and the fibrosis-4 (FIB-4) index are widely used to assess liver fibrosis. However, efficacies of these methods in the evaluation of hepatic functional reserve remain unclear. In this study, we investigated the relationship between ARFI elastography combined with either AAR, APRI, or FIB-4 index and Child-Pugh (CP) class for the evaluation of hepatic functional reserve in patients with chronic hepatitis B (CHB)-related cirrhosis. METHODS: The shear wave velocities of 104 patients with clinically confirmed CHB-related cirrhosis were determined using the ARFI; and clinical serum markers (e.g. ALT, AST, PLT) were used to calculate the AAR, APRI, and FIB-4 index. Cirrhosis patients were scored according to their CP class. The ARFI, AAR, APRI, and FIB-4 index were compared with the CP class. The efficacy of each indicator in diagnosis was analyzed using the receiver operating characteristic (ROC) curve and the ARFI combined with either the AAR, APRI, or FIB-4 index, which is used to predict decompensated cirrhosis. RESULTS: No significant differences were observed in gender and age among CP classes A, B, and C patients (p>0.05). The ARFI values and the AAR, APRI, and FIB-4 index of patients with CP classes A, B, and C were significantly different (p<0.05). With an increasing CP class, the ARFI, AAR, APRI, and FIB-4 values increased. The correlation between the ARFI and the CP class was stronger than that between the AAR, APRI, and FIB-4 index and the CP class. The area under the ROC curve for the diagnosis of decompensated cirrhosis using the ARFI was 0.841, which was higher than that for the AAR, APRI, and FIB-4 index. According to the area under the curve results, no significant differences were found when the ARFI was combined with either the AAR, APRI, or FIB-4 index and when the ARFI alone was used. CONCLUSIONS: The ARFI value has a strong correlation with the CP class. Therefore, ARFI elastography complements CP class in the assessment of the hepatic functional reserve in patients with CHB-related cirrhosis.