RESUMO
INTRODUCTION: The impact of longitudinal changes in different body components measured via body composition analysis (BCA) on liver-related outcomes in patients with cirrhosis is poorly understood. We evaluated the prognostic relevance of longitudinal changes in body composition over one year in patients with cirrhosis. METHODS: This was a follow-up study of a randomized controlled trial evaluating changes in bone density measured via dual energy X-ray absorptiometry (DEXA) upon vitamin D supplementation. Patients with available anthropometric indices, fat mass (FM), fat-free mass (FFM), bone-density at lumbar spine (LD) and left femur-neck (FD) (assessed by T score) at two time points one year apart were assessed for outcomes. The prognostic relevance of change in parameters such as ΔFM, ΔFFM, ΔLD and ΔFD over one year was assessed and compared with baseline model for end-stage liver disease (MELD) score. RESULTS: Patients with cirrhosis (n=112) (mean age 41.8±12 years, 58.5% males) were followed up for median duration of 5.7 years interquartile range [IQR 3.5-5.7], with five-year survival rate of 77%. On serial BCA, ΔLD (p=0.029) and ΔFD (p=0.003) emerged as significant predictors of survival, whereas ΔFM (p=0.479), ΔFFM (p=0.245) and ΔBMI (p=0.949) were not. The area under curve of ΔLD and MELD score for predicting survival was 0.636 (0.5-0.773) and 0.664 (0.555-0.773), respectively. ΔFD<0.1 over one year had sensitivity and specificity of 70.4% and 56.5% to predict poor survival. The combination of ΔFD, MELD and ascites predicted five-year survival with an optimism-corrected c-statistic of 0.785. CONCLUSION: Among body composition parameters, changes in bone mineral density correlate best with survival and have prognostic relevance similar to that of ascites and MELD score.
Assuntos
Absorciometria de Fóton , Composição Corporal , Densidade Óssea , Cirrose Hepática , Humanos , Masculino , Feminino , Cirrose Hepática/mortalidade , Cirrose Hepática/fisiopatologia , Cirrose Hepática/complicações , Adulto , Pessoa de Meia-Idade , Seguimentos , Prognóstico , Estudos Longitudinais , Taxa de Sobrevida , Vitamina D/sangue , Fatores de Tempo , Estudo de Prova de ConceitoRESUMO
Hepatic fibrosis is a spontaneous wound-healing response triggered by chronic liver injury. Pien Tze Huang (PZH), a traditional Chinese herbal medicine, has been widely used to treat various hepatic diseases in Asia. We used a CCl4-induced mouse model to establish a PZH group of hepatic fibrosis mice treated with PZH and a control group of hepatic fibrosis mice without any treatment. We performed RNA-seq and mass spectrometry sequencing to investigate the mechanism of the PZH response in hepatic fibrosis and identified multiple differentially expressed transcripts (DETs) and proteins (DEPs) that may be drug targets of PZH. Liver functional indices, including serum albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly decreased in the PZH treatment group (P < 0.05) in the eighth week. Hematoxylin-eosin (HE), Masson and Sirius red staining demonstrated that PZH significantly inhibited infiltration of inflammatory cells and collagen deposition. A total of 928 transcripts and 138 proteins were differentially expressed in PZH-treated mice compared to the control group. Gene Ontology (GO) enrichment analysis suggested that PZH may alleviate liver injury and fibrosis by enhancing the immune process. Taken together, our results revealed that multiple DETs and DEPs may serve as drug targets of PZH in hepatic fibrosis patient in future clinical practice.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , RNA Longo não Codificante/genética , Animais , Análise por Conglomerados , Medicamentos de Ervas Chinesas/farmacologia , Redes Reguladoras de Genes , Sistema Imunitário/metabolismo , Fígado/fisiopatologia , Cirrose Hepática/fisiopatologia , Testes de Função Hepática , Masculino , Camundongos Endogâmicos C57BL , Fases de Leitura Aberta/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coloração e RotulagemRESUMO
BACKGROUND AND AIM: Sarcopenia is considered an important risk factor for morbidity and mortality in liver cirrhosis. Beta-hydroxy-beta-methylbutyrate (HMB) has the potential to increase muscle mass and performance by stimulating protein synthesis and reducing muscle catabolism. The present study aimed at evaluating the effect of HMB supplementation on muscle mass and function in patients with liver cirrhosis. Changes in frailty during the study were also estimated, and the safety of HMB supplementation was verified. METHODS: This is a randomized, single-blind, placebo-controlled pilot trial. Twenty-four patients (14 HMB and 10 placebo) affected by liver cirrhosis were enrolled in the study. Each patient received dedicated counseling, which included nutrition and physical activity recommendations for chronic liver disease patients. Patients were randomized to receive 3 g/day of HMB or placebo (sorbitol powder) for 12 consecutive weeks. A diet interview, anthropometry, electrical bioimpedance analysis (BIA), quadriceps ultrasound, physical performance battery, Liver Frailty Index (LFI), and cognitive tests were completed at enrolment (T0), at 12 weeks (T1), and 24 weeks after enrolment (T2). RESULTS: At baseline, the two groups were similar in demography, severity of liver disease, muscle mass, muscle function, and cognitive tests. LFI at baseline was higher in patients in the HMB group vs. those in the placebo group (4.1 ± 0.4 vs. 3.4 ± 0.6, p < 0.01). After treatment, a statistically significant increase in muscle function was seen in the HMB group (chair stand test: 14.2 ± 5 s vs. 11.7 ± 2.6 s, p < 0.05; six-minute walk test: 361.8 ± 68 m vs. 409.4 ± 58 m, p < 0.05). Quadriceps muscle mass measured by ultrasound also increased (4.9 ± 1.8 vs. 5.4 ± 1.8 mm, p < 0.05) after HMB, while LFI decreased (4.1 ± 0.4 vs. 3.7 ± 0.4, p < 0.05). HMB was well tolerated by patients, and no adverse events were documented. CONCLUSIONS: Our study suggests the efficacy of 12-week beta-hydroxy-beta-methylbutyrate supplementation in promoting improvements in muscle performance in compensated cirrhotic patients. LFI was also ameliorated. Further studies with a greater number of patients are required to reinforce this hypothesis.
Assuntos
Suplementos Nutricionais , Cirrose Hepática/terapia , Força Muscular/efeitos dos fármacos , Sarcopenia/prevenção & controle , Valeratos/administração & dosagem , Antropometria , Impedância Elétrica , Exercício Físico/fisiologia , Feminino , Fragilidade/etiologia , Fragilidade/prevenção & controle , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Projetos Piloto , Sarcopenia/etiologia , Método Simples-Cego , Resultado do TratamentoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries. Coffee is one of the most consumed beverages in the world and has been shown to be beneficial in limiting progression in chronic liver disease in general. However, research surrounding the impact of coffee consumption on NAFLD progression is limited. This systematic review aimed to investigate the relationship between coffee consumption and the progression of liver disease, specifically for cases of NAFLD. MEDLINE, EMBASE, CINAHL, the Cochrane Library, and Scopus were searched for published studies that evaluated the effects of coffee consumption on the progression of NAFLD. The results are presented in a narrative synthesis with principal summary measures, including odds ratios, p-values, and differences in mean coffee intake in relation to severity of NAFLD. Five studies met the inclusion criteria and were included in this review. There was no trial evidence among NAFLD patients, rather all studies were of a cross-sectional design. Using the Academy of Nutrition and Dietetics Quality Criteria Checklist, four studies received a positive rating, with the remaining study receiving a neutral rating. Overall, four out of the five studies reported a statistically significant relationship between coffee consumption and the severity of fibrosis. Methods around capturing and defining coffee consumption were heterogeneous and therefore an effective dose could not be elucidated. Results suggest that higher coffee consumption is inversely associated with the severity of hepatic fibrosis in individuals with NAFLD. However, further research is required to elucidate the optimum quantity and form/preparation of coffee required to exert this hepatoprotective role.
Assuntos
Café , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Cafeína , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Razão de Chances , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Central serous chorioretinopathy (CSCR) and liver cirrhosis share numerous risk factors and may have possible connections. We aimed to investigate whether patients with liver cirrhosis and the severity of cirrhosis have an increased incidence of CSCR. METHODS: This population-based retrospective cohort study was conducted by collecting data from the Taiwan National Health Insurance Research Database from January 1, 2000, to December 31, 2015. We included patients who were newly diagnosed with cirrhosis and selected an equal number of sex- and age-matched control subjects. The effect of cirrhosis on the risk of CSCR was examined via a Cox proportional hazard regression analysis. The cumulative incidence of CSCR was assessed with the Kaplan-Meier method and the log-rank test. RESULTS: Both groups in this study comprised a total of 25 925 individuals. The cirrhotic patients had a significantly higher cumulative risk of developing CSCR in following years than patients without cirrhosis (log-rank test < 0.001). Furthermore, compared with noncirrhotic patients, the risk of CSCR was increased 3.59-fold (95% confidence interval [CI], 2.31-5.28) in cirrhotic patients with complications, and 2.34-fold (95% CI, 1.27-3.24) in cirrhotic patients without complications. Additionally, male sex, springtime, diabetes mellitus, hepatitis B virus, and hepatitis C virus statistical significantly increased the incidence of CSCR. CONCLUSION: Cirrhosis is an independent indicator of CSCR. Among the cirrhotic population, patients with ascites and other complications have a higher incidence of CSCR than those with uncomplicated cirrhosis. Physicians should be observant when managing cirrhotic patients with visual disturbances.
Assuntos
Coriorretinopatia Serosa Central/epidemiologia , Cirrose Hepática/fisiopatologia , Adulto , Idoso , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Gravidade do Paciente , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taiwan/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Galectin-3 (Gal-3) is a ß-galactoside binding protein associated with many disease pathologies, including chronic inflammation and fibrogenesis. It has been implicated in the disease severity of NASH, although its precise role is unknown. Inhibition of Gal-3 has shown to improve and prevent fibrosis progression and has now reached phase III clinical trial in NASH patients. AREAS COVERED: This discusses the role of Gal-3 in NASH. It brings together the current findings of Gal-3 in NASH and hepatic fibrosis by analyzing recent data from animal model studies and clinical trials. EXPERT OPINION: Gal-3 inhibitors, in particular, Belapectin (GR-MD-02), have shown promising results for NASH with advanced fibrosis. In a phase 2 trial, Belapectin did not meet the primary endpoint. However, a sub-analysis of Belapectin among a separate group of patients without esophageal varices showed 2 mg/kg of GR-MD-02 reduced HVPG and the development of new varices. A subsequent study is under way, aiming to replicate the positive findings in phase 2 and demonstrate greater efficacy. If Belapectin is shown to be effective, it will be coupled with other drugs that target steatohepatitis to maximize efficacy and disease reversal.
Assuntos
Proteínas Sanguíneas/antagonistas & inibidores , Galectinas/antagonistas & inibidores , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Pectinas/administração & dosagem , Pectinas/farmacologia , Índice de Gravidade de DoençaRESUMO
Chronic liver diseases caused by various pathogenesis are marked by inflammatory infiltration and wound healing reaction, while their normal regeneration ability is impaired. The unbalance between the generation and the degradation of extracellular matrix (ECM) leads to collagen accumulation and develops into liver fibrosis. Inflammation, oxidative stress, and autophagy interact closely in the pathogenesis of hepatic fibrosis. Reactive Oxygen Species (ROS) can not only stimulate Kupffer cells to release massive inflammatory factors, but induce autophagy. However, the latter may suppress inflammatory reaction by inhibiting proinflammatory complex formation directly, and removing damaged organelles or pathogenic microorganism indirectly. At present, effective anti-fibrosis drugs are still lacking. Previous studies have found various natural compounds enabled liver protection through anti-inflammatory, antioxidant, and other mechanisms. In recent years, autophagy, a vital life activity, has been found to be involved in the mechanism of liver fibrosis. As a new target, developing anti-liver fibrosis drugs that regulate the activity of autophagy is very promising. In this review, we summarize the latest studies about natural compounds in the treatment of liver fibrosis by regulating autophagy.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Cirrose Hepática/fisiopatologia , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Elastography provides significant information on staging of fibrosis in patients with liver disease and may be of some value in assessing steatosis. However, there remain questions as to the role of steatosis and fibrosis as cofactors influencing the viscoelastic measurements of liver tissues, particularly shear wave speed (SWS) and shear wave attenuation (SWA). In this study, by employing the theory of composite elastic media as well as two independent experimental measurements on oil-in-gelatin phantoms and also finite element simulations, it is consistently shown that fat and fibrosis jointly influence the SWS and SWA measurements. At a constant level of fat, fibrosis stages can influence the SWA by factors of 2-4. Moreover, the rate of increase in SWA with increasing fat is strongly influenced by the stages of fibrosis; softer background cases (low fibrosis stages) have higher rate of SWA increase with fat than those with stiffer moduli (higher fibrosis stages). Meanwhile, SWS results are influenced by the presence of fat, however the degree of variability is more subtle. The results indicate the importance of jointly considering fat and fibrosis as contributors to SWS and SWA measurements in complex liver tissues and in the design and interpretation of clinical trials.
Assuntos
Técnicas de Imagem por Elasticidade/métodos , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/fisiopatologia , Imagens de Fantasmas , Fenômenos Biomecânicos , Óleo de Rícino , Fibrose , Gelatina , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/fisiopatologia , Prognóstico , ViscosidadeRESUMO
BACKGROUND AND OBJECTIVE: Liver cirrhosis (LC), the major pathway for the progression and development of chronic liver disease, is an advanced stage of liver disease. It is the third most common chronic noncommunicable disease after cardiovascular diseases and malignant tumors. Tanshinone IIA (Tan), an extract of Salvia miltiorrhiza (S. miltiorrhiza), has been proven to promote the proliferation and differentiation of stem cells. Moreover, its protective effect in liver injury has received widespread attention. The present study investigated whether Tan plays a therapeutic role in LC by promoting endogenous stem cell proliferation and differentiation. MATERIALS AND METHODS: LC models were established by intraperitoneal injection of an olive oil solution containing 50 % carbon tetrachloride (CCL4) combined with 10 % alcohol in the drinking water. After successful model establishment, the animals were randomly divided into four groups and injected with physiological saline or low-, medium-, or high-dose (10, 20, or 40 mg/kg) Tan for seven consecutive days. The protective effect of Tan on LC was observed by western blotting, serological examination and histopathological staining. Furthermore, immunofluorescence double-labeling of 5-bromo-2-deoxyuridine (BrdU) and the liver cell markers albumin and CK-18 or the liver stem cell markers EPCAM and OV-6 was used to evaluate the proliferation and differentiation of endogenous liver stem cells. RESULTS: We confirmed successful establishment of the LC model by observing transaminase levels and hematoxylin-eosin (HE) and Masson staining of liver sections in CCL4-treated and healthy rats. After Tan treatment, HE and Masson staining of paraffin sections of liver tissue showed that Tan treatment significantly improved histological injury to the liver. Serological tests showed that albumin-bilirubin (ALBI) scores and models for end-stage liver disease (MELD) were lower. Immunofluorescence and immunohistochemical staining showed that the newly proliferated cells were colocalized with ALB, OV-6, EPCAM, and CK-18, indicating that new expression of these markers occurred after Tan injection. All results were most significant in the medium-dose treatment group. CONCLUSION: Tan can alleviate liver injury induced by CCL4 combined with alcohol in rats and plays a therapeutic role in LC by promoting the proliferation and differentiation of endogenous liver stem cells.
Assuntos
Abietanos/farmacologia , Cirrose Hepática/tratamento farmacológico , Salvia miltiorrhiza/química , Células-Tronco/citologia , Abietanos/administração & dosagem , Abietanos/isolamento & purificação , Animais , Tetracloreto de Carbono , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cirrose Hepática/fisiopatologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Vitamin B-6 and glutathione (GSH) are antioxidant nutrients, and inadequate vitamin B-6 may indirectly limit glutathione synthesis and further affect the antioxidant capacities. Since liver cirrhosis is often associated with increased oxidative stress and decreased antioxidant capacities, we conducted a double-blind randomized controlled trial to assess the antioxidative effect of vitamin B-6, GSH, or vitamin B-6/GSH combined supplementation in cirrhotic patients. We followed patients after the end of supplementation to evaluate the association of vitamin B-6 and GSH with disease severity. In total, 61 liver cirrhosis patients were randomly assigned to placebo, vitamin B-6 (50 mg pyridoxine/d), GSH (500 mg/d), or B-6 + GSH groups for 12 weeks. After the end of supplementation, the condition of patient's disease severity was followed until the end of the study. Neither vitamin B-6 nor GSH supplementation had significant effects on indicators of oxidative stress and antioxidant capacities. The median follow-up time was 984 d, and 21 patients were lost to follow-up. High levels of GSH, a high GSH/oxidized GSH ratio, and high GSH-St activity at baseline (Week 0) had a significant effect on low Child-Turcotte-Pugh scores at Week 0, the end of supplementation (Week 12), and the end of follow-up in all patients after adjusting for potential confounders. Although the decreased GSH and its related enzyme activity were associated with the severity of liver cirrhosis, vitamin B-6 and GSH supplementation had no significant effect on reducing oxidative stress and increasing antioxidant capacities.
Assuntos
Antioxidantes/administração & dosagem , Suplementos Nutricionais , Glutationa/administração & dosagem , Cirrose Hepática/terapia , Vitamina B 6/administração & dosagem , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Systemic inflammation and severe fibrosis can reduce serum zinc levels, while zinc supplementation is reported to improve the prognosis of patients with chronic liver disease (CLD). OBJECTIVES: We aimed to investigate the clinical application of serum zinc in patients with CLD and the anti-infective mechanism of zinc supplementation. METHODS: Based on the serum zinc level, 149 CLD patients were divided into 3 groups and their clinical parameters were compared. In in-vitro experiments, microbial isolates derived from patients were used to stimulate human liver non-parenchymal cells, and the zinc sulfate solution was added in certain experiments. The effect of zinc was compared by LDH and thromboxane A2 levels in the cell supernatant. RESULT: Compared with other groups, patients with low serum zinc levels had significantly higher C-reactive protein (CRP), total bilirubin, INR, creatinine, and MELD scores, while albumin and GOT levels were reduced. Only CRP and albumin were significantly correlated with serum zinc in both low and normal-zinc groups. Bacterial isolates significantly increased LDH levels in Kupffer cells (KCs) and stellate cells but had no effect on sinusoidal endothelial cells, whereas zinc pretreatment protected KCs but not stellate cells. Thromboxane A2 secreted by KCs can also be induced by bacterial stimulation, accompanied by increased gene expression of Myd88, MAPK and NF-kB, while zinc pretreatment can attenuate that. CONCLUSION: Serum zinc levels can be used to estimate infection and liver fibrosis in CLD patients. As a new antibacterial weapon, zinc supplementation acts on KCs through Myd88-MAPK related pathways.
Assuntos
Células de Kupffer/metabolismo , Cirrose Hepática/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Sulfato de Zinco/administração & dosagem , Adulto , Idoso , Doença Crônica , Feminino , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/microbiologia , Cirrose Hepática/fisiopatologia , Hepatopatias/microbiologia , Hepatopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tromboxano A2/metabolismo , Zinco/sangue , Sulfato de Zinco/farmacologiaRESUMO
The hepatorenal syndrome (HRS) is only a part of the wide spectrum of renal injury in patients with end-stage liver cirrhosis. Besides that, the advanced liver disease itself, or its underlying causes, as well as comorbidities, like diabetes mellitus, adiposity and arterial hypertension, can directly cause parenchymal renal insults (bile acid nephropathy, ischemic tubular injury, diabetic/hypertensive nephropathy, hepatitis B- and C-associated glomerulonephritis etc.). This kind of kidney injury is collectively described as non-hepatorenal syndrome AKI (non-HRS AKI. Beyond that, accumulating evidence highlights the role of systemic inflammation as an important common factor in the pathogenesis of decompensated liver cirrhosis, acute in chronic liver failure (ACLF) and renal dysfunction.In this review, we discuss recent data about definition, classification and pathophysiology of HRS, HRS-AKI and Non-HRS-AKI and exploit in this regard the diagnostic and prognostic potential of respective newer serum and urine markers.
Assuntos
Injúria Renal Aguda , Síndrome Hepatorrenal , Cirrose Hepática , Injúria Renal Aguda/fisiopatologia , Síndrome Hepatorrenal/fisiopatologia , Humanos , Rim , Cirrose Hepática/fisiopatologiaRESUMO
Context: Fuzheng Huayu recipe (FZHY) combined with entecavir (ETV) is used to treat the cirrhosis caused by chronic hepatitis B (CHB) infection.Objective: To investigate the effect of FZHY on ETV pharmacokinetics under different conditions.Materials and methods: A model of liver fibrosis was created by intraperitoneal injection of dimethylnitrosamine (DMN; 10 µg/kg) for 4 weeks in Wistar rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to determine the blood concentration of ETV. Pharmacokinetic characteristics of ETV (0.9 mg/kg) were investigated after co-administration with FZHY (0.55 g/kg) at certain time intervals in normal and model rats.Results: The analytical method for ETV was validated at 0.5-50 µg/L with a correlation coefficient = 0.9996, lower limit of quantitation of 0.5 µg/L and mean accuracy of 104.18 ± 9.46%. Compared with the ETV-N group, the pharmacokinetic parameters of the EF-2 group did not change significantly, but that of the EF-0 group decreased in Cmax to 27.38 µg/L, in AUC0-t from 323.84 to 236.67 µg/h/L, and a delay in Tmax from 0.75 to 6.00 h; that of the EF-0 group presented a decrease in Cmax of 61.92%, delay in t1/2 of 2.45 h and delay in Tmax of 2.92 h. The t1/2e and Vd/F of ETV were increased significantly to 8.01 h and 24.38 L/kg in the ETV-M group.Conclusions: The effects of FZHY on ETV pharmacokinetics were diminished with an increase of interval time. The best time to administer both drugs is >2 h apart.
Assuntos
Antivirais/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Guanina/análogos & derivados , Cirrose Hepática/fisiopatologia , Animais , Antivirais/administração & dosagem , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/métodos , Dimetilnitrosamina , Esquema de Medicação , Medicamentos de Ervas Chinesas/farmacologia , Guanina/administração & dosagem , Guanina/farmacologia , Meia-Vida , Interações Ervas-Drogas , Masculino , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem/métodosRESUMO
Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.
Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/prevenção & controle , Hepatopatias/fisiopatologia , Osteoporose/etiologia , Osteoporose/prevenção & controle , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/fisiopatologia , Cálcio/uso terapêutico , Colestase/complicações , Colestase/fisiopatologia , Doença Crônica , Dieta Saudável , Suplementos Nutricionais , Difosfonatos/uso terapêutico , Terapia por Exercício , Terapia de Reposição Hormonal , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Hepatopatias/complicações , Osteogênese , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Fatores de Risco , Vitamina D/uso terapêuticoRESUMO
BACKGROUND: To facilitate translational drug development for liver fibrosis, preclinical trials need to be run in parallel with clinical research. Liver function estimation by gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI) is being established in clinical research, but still rarely used in preclinical trials. We aimed to evaluate feasibility of DCE-MRI indices as translatable biomarkers in a liver fibrosis animal model. METHODS: Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (200 mg, 150 mg, and saline for the high-dose, low-dose, and control groups, respectively). Subsequently, DCE-MRI was performed to measure: relative liver enhancement at 3-min (RLE-3), RLE-15, initial area-under-the-curve until 3-min (iAUC-3), iAUC-15, and maximum-enhancement (Emax). The correlation coefficients between these MRI indices and the histologic collagen area, indocyanine green retention at 15-min (ICG-R15), and shear wave elastography (SWE) were calculated. Diagnostic performance to diagnose liver fibrosis was also evaluated by receiver-operating-characteristic (ROC) analysis. RESULTS: Animal model was successful in that the collagen area of the liver was the largest in the high-dose group, followed by the low-dose group and control group. The correlation between the DCE-MRI indices and collagen area was high for iAUC-15, Emax, iAUC-3, and RLE-3 but moderate for RLE-15 (r, - 0.81, - 0.81, - 0.78, - 0.80, and - 0.51, respectively). The DCE-MRI indices showed moderate correlation with ICG-R15: the highest for iAUC-15, followed by iAUC-3, RLE-3, Emax, and RLE-15 (r, - 0.65, - 0.63, - 0.62, - 0.58, and - 0.56, respectively). The correlation coefficients between DCE-MRI indices and SWE ranged from - 0.59 to - 0.28. The diagnostic accuracy of RLE-3, iAUC-3, iAUC-15, and Emax was 100% (AUROC 1.000), whereas those of RLE-15 and SWE were relatively low (AUROC 0.777, 0.848, respectively). CONCLUSION: Among the gadoxetate-enhanced DCE-MRI indices, iAUC-15 and iAUC-3 might be bidirectional translatable biomarkers between preclinical and clinical research for evaluating histopathologic liver fibrosis and physiologic liver functions in a non-invasive manner.
Assuntos
Meios de Contraste/administração & dosagem , Gadolínio DTPA/administração & dosagem , Cirrose Hepática/diagnóstico por imagem , Fígado/fisiopatologia , Animais , Área Sob a Curva , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estudos de Viabilidade , Humanos , Fígado/diagnóstico por imagem , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/fisiopatologia , Testes de Função Hepática , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Tioacetamida/efeitos adversosRESUMO
Liver disease and nutritional status affect each other mutually. Hepatic function is impaired by malnutrition and can be improved by nutrition therapy. Liver cirrhosis leads to prognostically relevant malnutrition in a stage dependent manner. Protein depletion and sarcopenia are its key features. Patients with liver cirrhosis should undergo systematic screening for risk of malnutrition and if positive sarcopenia should be assessed and a nutrition plan devised. In cirrhotic patients, spontaneous food intake frequently does not meet requirements and prolonged (>â12âh) periods of fasting must be avoided. In a stepwise fashion nutritional counseling, oral nutritional supplements, enteral tube feeding and parenteral nutrition as third-line-therapy should be used. In cirrhotic patients, nutrition therapy can improve morbidity and mortality by ensuring the adequate provision of energy, protein and micronutrients.
Assuntos
Cirrose Hepática , Apoio Nutricional , Humanos , Cirrose Hepática/dietoterapia , Cirrose Hepática/fisiopatologia , Transplante de Fígado , Desnutrição , Guias de Prática Clínica como Assunto , SarcopeniaRESUMO
INTRODUCTION AND OBJECTIVES: Liver cirrhosis is characterized by increased intrahepatic resistance, splanchnic vasodilation/angiogenesis, and formation of portosystemic collateral vessels. Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage. Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients. It is also known that folic acid supplementation reverses the effects of homocysteine. However, the treatment effect in cirrhosis has yet to be investigated. MATERIAL AND METHODS: Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (CBDL). The CBDL rats randomly received (1) vehicle; (2) dl-homocysteine thiolactone (1g/kg/day); (3) dl-homocysteine thiolactone plus folic acid (100mg/kg/day); or (4) folic acid. On the 29th day, hemodynamic parameters, liver and renal biochemistry, protein expressions of proangiogenic factors, mesenteric vascular density and portosystemic shunting were evaluated. RESULTS: In the cirrhotic rats, homocysteine increased mesenteric vascular density and the severity of shunting. It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor (VEGF) and phosphorylated-endothelial nitric oxide synthase (p-eNOS). These effects were reversed by folic acid treatment (P<0.05). CONCLUSION: Folic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats, which may be related to down-regulation of the VEGF-NO signaling pathway.
Assuntos
Circulação Colateral/efeitos dos fármacos , Ácido Fólico/farmacologia , Homocisteína/análogos & derivados , Cirrose Hepática/fisiopatologia , Neovascularização Patológica/induzido quimicamente , Sistema Porta/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Complexo Vitamínico B/farmacologia , Animais , Ducto Colédoco , Hemodinâmica/efeitos dos fármacos , Homocisteína/farmacologia , Ligadura , Cirrose Hepática/complicações , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Sistema Porta/patologia , Ratos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.
Assuntos
Encefalopatia Hepática/fisiopatologia , Cirrose Hepática/fisiopatologia , Amônia/metabolismo , Gânglios da Base/fisiopatologia , Cerebelo/fisiopatologia , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/metabolismo , Humanos , Inflamação/fisiopatologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Manganês/metabolismo , Neurotransmissores/antagonistas & inibidores , Tálamo/fisiopatologia , Ácido gama-Aminobutírico/metabolismoRESUMO
RATIONALE AND OBJECTIVES: As a special movement disorder, hepatic myelopathy (HM) is characterized by spastic paraperesis and may be secondary to transjugular intrahepatic portosystemic shunt (TIPS). The prediction and diagnosis of HM is difficult due to largely unknown neuropathological underpinnings and a lack of specific biomarkers. We aimed to delve into the alterations in motor system of HM patients' brain and their potential clinical implication. MATERIAL AND METHODS: Twenty-three patients with HM and 23 without HM after TIPS and 24 demographically matched healthy controls were enrolled. High-spatial-resolution structural imaging and functional data at rest were acquired. Motor areas were included as seed regions for functional connectivity analysis. Then, we performed brain volume analysis. RESULTS: We found decreased right supplementary motor area (SMA)-seeded functional connectivity with bilateral insula, thalamus and midbrain, left cerebellum and middle temporal gyrus, and right middle cingulate gyrus in HM compared to non-HM patients (p < 0.001). The right insula revealed decreased volume (p < 0.001), and white matter volume reduced in the right corona radiata beneath the right SMA (p < 0.001) in HM relative to non-HM patients. Furthermore, the strength of right SMA-seeded connectivity with insula was positively correlated with folic acid level in HM patients (râ¯=â¯0.60, p = 0.03), showing an accuracy of 0.87 to distinguish HM from non-HM. CONCLUSION: Our study demonstrates the HM-specific dysconnectivity with an anatomical basis, and its correlation with laboratory findings and diagnostic value. Detecting these abnormalities might help to predict and diagnose post-TIPS HM.
Assuntos
Encefalopatias/patologia , Córtex Motor/patologia , Derivação Portossistêmica Transjugular Intra-Hepática , Doenças da Medula Espinal/patologia , Biomarcadores/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Encefalopatias/fisiopatologia , Mapeamento Encefálico/métodos , Estudos de Casos e Controles , Feminino , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Tamanho do Órgão/fisiologia , Paraparesia Espástica/patologia , Paraparesia Espástica/fisiopatologia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/fisiopatologia , Doenças da Medula Espinal/fisiopatologia , Substância Branca/patologia , Substância Branca/fisiopatologiaRESUMO
BACKGROUND/PURPOSE: Although coffee consumption has been associated with decreased risk of liver fibrosis progression, cirrhosis or hepatocellular carcinoma in patients with HCV infection or fatty liver diseases, its effect on hepatitis B patients remains unclear. We aimed to examine the effect of coffee consumption on liver fibrosis progression and cirrhosis-related complications in patients with chronic HBV infection. METHODS: Coffee consumption was assessed in 2604 participants who were previously recruited from a population-based GERD survey. The primary endpoints of this study were the impact of coffee consumption on the development of cirrhosis-related complications, including liver cirrhosis, esophageal varices, or hepatocellular carcinoma at the end of 5-year follow-up. The secondary endpoints were the declines of serum predicting indices of liver fibrosis (AST/ALT, APRI, FIB-4, Hui score) or liver function tests (AST, ALT). RESULTS: 328 patients with chronic HBV infection were enrolled into this study. At baseline, coffee consumption was associated with higher education level, more frequent tobacco use and normal blood pressure (p < 0.05 for all). Patients with higher coffee consumption had a significant lower serum AST, APRI and FIB-4 index value than non-coffee drinkers [adjusted HR 0.30, 95% CI(0.11-0.82) for AST; 0.30, 95% CI (0.11-0.84) for APRI; 0.30, 95% CI (0.13-0.69) for FIB-4]. However, higher coffee consumption didn't change serum AST levels, APRI, FIB-4 index values or incidences of cirrhosis-related complications at the end of 5-year follow-up. CONCLUSION: Coffee consumption was not associated with fibrosis progression or HCC risk in chronic hepatitis B patients over the 5-year observation period.