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1.
Intern Med ; 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38925969

RESUMO

This case report describes a patient who received hormone replacement therapy for secondary panhypopituitarism and subsequently developed diabetes. His physician decided to discontinue growth hormone (GH) replacement, which was previously deemed contraindicated. Following the diagnosis of fatty liver, the patient began to exhibit liver damage that progressed over the ensuing years, ultimately leading to cirrhosis. Common factors linked to cirrhosis were excluded, leading to the belief that GH deficiency over several years was the primary contributor to cirrhosis. Therefore, when treating patients with GH insufficiency and diabetes, clinicians should carefully consider the potential implications of GH replacement therapy.

2.
J Clin Med ; 12(16)2023 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-37629453

RESUMO

BACKGROUND/AIMS: Although the World Health Organization declared the end of the public health emergency of international concern focusing on COVID-19 in May 2023, this bothersome virus continues to mutate, and the possibility of the emergence of mutant strains with high infectivity and severe disease rates has not disappeared. Thus, medical evidence must be accumulated, which is indispensable for protecting both patients under immunosuppressive treatments and the healthy population. This study examined SARS-CoV-2 vaccination responses in Japanese patients with autoimmune hepatitis (AIH) compared with healthy controls. METHODS: This observational study registered 22 patients with histologically diagnosed AIH and 809 healthy controls in our hospital. Their Elecsys anti-SARS-CoV-2 spike antibody concentrations before and after vaccination were evaluated. RESULTS: In this study, 72.7% and 18.2% of patients with AIH received steroids and azathioprine, respectively. Significant negative correlations were found between age and anti-SARS-CoV-2 spike antibody concentration in both groups; however, no sex differences were found. Although anti-SARS-CoV-2 spike antibody concentration was drastically augmented after the second vaccination (p < 0.05) in the AIH group, these levels were significantly lower than those in the controls (p < 0.05). In the age- and sex-matched analysis, the population ratio with a minimum response (≤100 binding antibody units (BAU/mL) was higher among patients with AIH than among controls 26 weeks after the second vaccination (44% vs. 7%, p < 0.05). CONCLUSIONS: The anti-SARS-CoV-2 spike antibody concentration in AIH patients was significantly lower than that in controls after the second vaccination. Continued and widespread vaccination, particularly for patients requiring medical immunomodulation, is recommended.

3.
Indian J Gastroenterol ; 41(2): 169-180, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35279807

RESUMO

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model. METHODS: Fischer 344 rats were fed with choline-deficient L-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated. RESULTS: OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-ß1 (TGF-ß1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet-induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-ß1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel. CONCLUSIONS: OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Hepatopatia Gordurosa não Alcoólica , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Humanos , Cirrose Hepática/genética , Losartan/farmacologia , Losartan/uso terapêutico , Metaloproteinase 2 da Matriz , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Mensageiro/metabolismo , Ratos , Inibidor Tecidual de Metaloproteinase-1/uso terapêutico , Receptor 4 Toll-Like , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/uso terapêutico
4.
Int J Mol Sci ; 22(21)2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34769332

RESUMO

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH histological features and equol production. In an animal model, obese OLETF rats were intraperitoneally injected with a porcine serum to augment liver fibrogenesis. Equol-rich soy product, SE5-OH was orally administered during the experimental period. Treatment with SE5-OH markedly attenuated the development of liver fibrosis and expression of alpha-smooth muscle actin. In clinical research, 38 NAFLD patients (13 men and 25 women) were included. The degree of fibrosis and ballooning in equol-nonproducers was significantly higher than in equol-producers in women. The percentage of nonproducers with NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers. None of the histological features were significantly different between nonproducers and producers in men. Decision tree analysis identified predictors for NAS ≥ 5 in women. The status of equol production was the strongest predictor, followed by fasting glucose. Since equol can be noninvasively detected in urine, it can be applied as a screening tool for the progression of NASH in women.


Assuntos
Equol/metabolismo , Isoflavonas/farmacologia , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Feminino , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Endogâmicos OLETF , Suínos
5.
Medicine (Baltimore) ; 100(36): e27212, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516526

RESUMO

ABSTRACT: We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis.Patients (n = 193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n = 55) and non-alcoholic cirrhosis (NA; n = 138) groups, and those (n = 235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n = 92), non-alcoholic steatohepatitis-related (n = 27), and hepatitis C virus-related cirrhosis groups (n = 116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay.SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R = 0.64, P < .0001) and both sexes in group NA (male: R = 0.44, P = .0001; female: R = 0.35, P = .003). SMI-CT inversely correlated with the EA levels of the men in group A1 (R = -0.67, P < .0001) and myostatin levels in group NA (R = -0.53, P < .0001). Lower extremity SMI had a strong negative correlation with the EA levels of the men in group A1 (R = -0.58, P < .001), whereas upper extremity SMI showed an inverse trend with EA levels (R = -0.28, P = .08). SMI-CT also inversely correlated with the EA levels in groups A2 (R = -0.52, P = .003) and N (R = -0.67, P < .0001) and myostatin levels in group C (R = -0.65, P < .0001). Moreover, SMI-CT correlated with nutritional factors, including cholinesterase (R = 0.50, P = .005), zinc (R = 0.45, P = .01), branched amino acid-to-tyrosine ratio (R = 0.39, P = .02), and triglyceride (R = 0.33, P = .03) in group N.Sarcopenia risk factors differ among cirrhosis etiologies. Alcohol-induced, intestine-mediated peripheral endotoxemia could participate in sarcopenia development in patients with alcoholic cirrhosis.


Assuntos
Endotoxinas/metabolismo , Cirrose Hepática Alcoólica , Músculo Esquelético/metabolismo , Sarcopenia/epidemiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , Prevalência , Estudos Retrospectivos , Fatores de Risco , Sarcopenia/diagnóstico por imagem , Sarcopenia/etiologia , Tomografia Computadorizada por Raios X
6.
Medicines (Basel) ; 8(7)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34357155

RESUMO

Background: This study aimed to compare the diagnostic performance of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (γ-GTP) to assess the single and combined benefits of these biological markers for the detection of chronic excessive alcohol consumption in patients with alcoholic cirrhosis. Methods: Biological markers were determined in blood samples from patients with alcoholic cirrhosis (drinking group, n = 35; nondrinking group, n = 81). The prediction accuracy of %CDT alone, γ-GTP alone, and their combination for the detection of excessive alcohol consumption was determined in patients with alcoholic cirrhosis. Results: Serum total bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-GTP, and alkaline phosphatase levels and %CDT were significantly higher and serum albumin levels were significantly lower in the drinking group than in the nondrinking group. The combination of %CDT and γ-GTP compared with %CDT or γ-GTP alone showed a higher prediction accuracy. The combination of %CDT and γ-GTP exhibited a higher specificity than γ-GTP alone. However, in terms of sensitivity, no significant difference was found between single or combined markers. Conclusions: The combination of %CDT and γ-GTP is considered a useful biomarker of chronic excessive alcohol consumption in patients with alcoholic cirrhosis.

7.
World J Gastroenterol ; 26(45): 7232-7241, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33362379

RESUMO

BACKGROUND: Prediction of HAIC treatment response is important for improving the prognosis in patients with hepatocellular carcinoma (HCC). The progression of HCC is related to hypercoagulability and angiogenesis. It is known that ADAMTS13 and von Willebrand factor (VWF) are related to hypercoagulability. In addition, previous study reported that the association between ADAMTS13 and VWF, and angiogenesis via vascular endothelial growth factor (VEGF). Recently, ADAMTS13 and VWF have been associated with the prognosis in patients with various kinds of cancer undergoing chemotherapy. AIM: To investigate whether ADAMTS13 and VWF become useful biomarkers of treatment response in HCC patients before the initiation of HAIC treatment. METHODS: Seventy-two patients were enrolled in this study. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag) and VEGF levels were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were performed to determine the predictive factors of treatment response in patients with HCC undergoing HAIC treatment. RESULTS: ADAMTS13:AC levels in HCC patients with stable disease (SD) + partial response (PR) of HAIC treatment were significantly higher than those with progressive disease (PD) (P < 0.05). In contrast, VWF:Ag/ADAMTS13:AC ratio and VEGF levels in HCC patients with SD + PR were significantly lower than those with PD (both P < 0.05). Patients with high VWF:Ag/ADAMTS13:AC ratio (> 2.7) had higher VEGF levels than those with low ratio (≤ 2.7). Multivariable analysis revealed that VWF:Ag/ADAMTS13:AC ratio was a predictive factor of HAIC treatment response. CONCLUSION: VWF:Ag/ADAMTS13:AC ratio may become a useful biomarker of treatment response in HCC patients before the initiation of HAIC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína ADAMTS13 , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Prognóstico , Fator A de Crescimento do Endotélio Vascular , Fator de von Willebrand
8.
J Clin Med ; 9(11)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138335

RESUMO

A potential restriction of the Baveno VI consensus, which helps to avoid unnecessary endoscopies, is the limited availability of FibroScan. We aimed to identify serum fibrosis indices that might aid in ruling out the presence of high-risk varices in cirrhotic patients. This retrospective study included 541 consecutive patients with cirrhosis who underwent endoscopy and had data available for nine serum fibrosis indices, including platelet count, hyaluronic acid, 7S fragment of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, fibrosis index based on four factors (FIB-4), aspartate transaminase/platelet ratio index and enhanced liver fibrosis score. Optimal index cutoffs for predicting high-risk varices were calculated in an estimation cohort (n = 127) and evaluated in a validation cohort (n = 351). The diagnostic performance of the indices was assessed by receiver operating characteristic curve analysis. In the estimation cohort, a FIB-4 cutoff of 2.78 provided the greatest diagnostic accuracy in predicting both all-grade and high-risk varices. FIB-4 had a negative predictive value of 1.00 for high-risk varices in both cohorts, and 21.3% (27/127) and 14.8% (52/351) of the estimation and validation cohorts, respectively, avoided esophagogastroduodenoscopy; no high-risk varices were missed in either cohort. FIB-4 correctly identifies the absence of high-risk varices in patients with cirrhosis. Therefore, those with a FIB-4 of ≥2.78 should undergo esophagogastroduodenoscopy, and FIB-4 determination should be recommended every 6-12 months concurrently with the other blood tests until the index value reaches 2.78 in those with a FIB-4 of <2.78.

9.
Int J Mol Sci ; 21(15)2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32759852

RESUMO

The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut-liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-ß and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Rifaximina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Angiotensinas/genética , Animais , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
10.
J Clin Med ; 9(6)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481684

RESUMO

It is unclear whether the link between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) is mediated by common risk factors. We aimed to elucidate the association between NAFLD and CKD using propensity score (PS)-matched analysis. We assessed 3725 Japanese individuals, excluding those with hepatitis B or C infection and men and women who consumed >30 and >20 g/day of alcohol, respectively. Of these, we enrolled 1097 Japanese subjects with NAFLD diagnosed by ultrasonography and 1097 PS-matched subjects without NAFLD. The prevalence of CKD was higher in subjects with NAFLD than in those without NAFLD before PS matching, but there was no significant difference between these groups in terms of CKD prevalence after PS matching. There was no difference in the prevalence of CKD between those with and without NAFLD in the subgroup analyses. Logistic regression analysis demonstrated that obesity, hypertension, and hyperuricemia were independent predictors of CKD, but NAFLD was not independently associated with CKD. In subjects with NAFLD, obesity, hypertension, and hyperuricemia were independent predictors of CKD. Thus, the link between NAFLD and CKD may be mediated by common risk factors. We recommend screening for CKD when patients with NAFLD have the aforementioned comorbidities.

11.
JGH Open ; 4(3): 400-404, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32514444

RESUMO

BACKGROUND AND AIM: Hypothyroidism might play a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The association of subclinical hypothyroidism with NAFLD has been inconsistent. The relationship of NAFLD with thyroid function parameters and subclinical hypothyroidism was determined. METHODS: This cross-sectional study included 70 patients with subclinical hypothyroidism and 70 controls with euthyroidism matched according to gender, age, and body mass index (BMI). NAFLD was diagnosed via abdominal ultrasonography. The association between NAFLD and subclinical hypothyroidism was analyzed. RESULTS: The prevalence of NAFLD was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Multivariate analysis showed that subclinical hypothyroidism was an independent risk factor of NAFLD adjusted by metabolic-related factors, such as BMI, triglyceride, high-density lipoprotein-cholesterol, hypertension, and diabetes. Thyroid-stimulating hormone (TSH) was an independent risk factor of NAFLD adjusted by the same metabolic-related factors, but free thyroxine (FT4) was not a risk factor. The FIB-4 index, a noninvasive marker of liver fibrosis was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Compared with patients with euthyroidism, the proportion of the FIB-4 index ≥2.67 was significantly higher, and the proportion of the FIB-4 index <1.30 was lower in patients with subclinical hypothyroidism. CONCLUSIONS: TSH elevation even within the euthyroid range is an independent risk factor of NAFLD and may influence the progression of liver fibrosis, even with a normal FT4 level.

12.
Hepatol Res ; 50(9): 1101-1105, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32558192

RESUMO

AIMS: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). Lusutrombopag, an oral thrombopoietin receptor agonist, is used to reduce the risk of hemorrhage in patients with thrombocytopenia who are undergoing invasive procedures. Platelet transfusion was the standard treatment for thrombocytopenia; however, multiple platelet transfusions lead to the production of antiplatelet antibody. The effect of giving lusutrombopag three times or more has not been previously reported. In this study, we investigated the effect of lusutrombopag readministration in patients with thrombocytopenia. METHODS: This study included 14 patients (total, 24 readministrations) who received lusutrombopag two times or more. Changes in platelet counts were evaluated. Treatment response was defined as an increased platelet count of ≥20 000/µL after lusutrombopag treatment. RESULTS: Lusutrombopag was given twice in nine patients, three times in three patients, five times in one patient, and six times in one patient. An elevated platelet count of <20 000/µL was noted in only one of the 24 readministrations. There were no postoperative hemorrhagic complications, and no patient had an increased platelet count of >200 000/µL. One patient had a portal venous mural thrombus; however, he was asymptomatic, and the thrombus resolved after anticoagulant treatment, without recurrence. The comparison between the first, second, and third or more treatments showed there was no significant difference in platelet increase. CONCLUSION: Repeated treatment of lusutrombopag is effective for CLD patients with thrombocytopenia. Moreover, three or more treatments with lusutrombopag showed equal effect compared with one and two treatments with the medication.

13.
Microorganisms ; 8(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575352

RESUMO

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.

14.
J Clin Med ; 9(5)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32422875

RESUMO

Acute-on-chronic liver failure (ACLF) leads to systematic inflammatory response syndrome and multiple organ failure. This study investigated the relationship between endotoxin (Et) and ACLF with the aim of determining whether Et activity (EA) is useful as a predictive biomarker of ACLF development and whether rifaximin treatment decreased the risk of ACLF development. Two hundred forty-nine patients with liver cirrhosis were enrolled in this study. Et concentration was determined in the whole blood by a semiquantitative EA assay. Predictive factors of ACLF development and the risk of ACLF development with and without rifaximin treatment were identified by univariate and multivariate analysis using Fine and Gray's proportional subhazards model. EA level was higher in Child-Pugh class B than in class A patients, and class B patients had an increased risk of ACLF development compared with class A patients. Multivariate analysis showed that EA level was a predictive factor independently associated with ACLF development. Rifaximin decreased EA level and the risk of ACLF development in Child-Pugh class B patients. Et levels were associated with functional liver capacity and were predictive of ACLF development in cirrhotic patients. Rifaximin decreased Et level and the risk of ACLF development in advanced cirrhotic patients.

15.
Nutrients ; 12(4)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283773

RESUMO

We aimed to elucidate the effect of chronic alcohol consumption on fatty liver. We assessed the consumption of alcohol in 2429 Japanese males (mean age: 54.2 ± 9 years); they were classified according to average consumption into non-drinkers (ND), light drinkers (LD), moderate drinkers (MD), and heavy drinkers (HD). The prevalence of fatty liver was the lowest in the MD and highest in the ND group (p < 0.001), while obesity was not significantly different among the groups (p = 0.133). Elevated levels of alanine aminotransferase (ALT) were the lowest in the MD group (p = 0.011) along with resistance to insulin (homeostasis model assessment-insulin resistance (HOMA-IR)), which was highest in the ND group (p = 0.001). Chronic consumption of alcohol was independently and inversely associated with fatty liver and insulin resistance after adjusting for obesity, hypertension, fasting hyperglycemia, habit of drinking sweet beverages, physical activity, and age (odds ratios are as follows: ND, 1; LD, 0.682; MD, 0.771; HD, 0.840 and ND, 1; LD, 0.724; MD, 0.701; HD, 0.800, respectively). We found that regardless of the type of alcoholic beverage, chronic consumption of alcohol is inversely associated with insulin resistance and fatty liver in Japanese males. This study had limitations, most notably the lack of investigation into diet and nutrition.


Assuntos
Consumo de Bebidas Alcoólicas , Fígado Gorduroso/epidemiologia , Resistência à Insulina , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Povo Asiático , Estudos Transversais , Fígado Gorduroso/prevenção & controle , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Prevalência
16.
Int J Mol Sci ; 21(6)2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32245205

RESUMO

Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-ß1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH.


Assuntos
Canagliflozina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazóis/farmacologia , Tiazolidinas/farmacologia , Animais , Caderinas/genética , Caderinas/metabolismo , Canagliflozina/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Progressão da Doença , Sinergismo Farmacológico , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pirazóis/uso terapêutico , Ratos , Ratos Endogâmicos , Tiazolidinas/uso terapêutico , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Antibiotics (Basel) ; 9(4)2020 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-32235367

RESUMO

Rifaximin is a poorly absorbable antibiotic against hepatic encephalopathy (HE). This observational study aimed to elucidate the effect of rifaximin on intestinal permeability and gut microbiota in patients with decompensated cirrhosis. Thirty patients with decompensated cirrhosis were assessed by ammonia level, neuropsychological testing, endotoxin activity (EA), and serum proinflammatory cytokines at baseline and after four weeks of rifaximin treatment (1200 mg/day). Intestinal permeability was indicated by serum soluble CD163 (sCD163), mannose receptor (sMR), and zonulin levels. To evaluate the gut microbiome, 16S ribosomal RNA gene sequencing was applied. Rifaximin ameliorated hyperammonemia and cognitive dysfunction, although it did not change the serum proinflammatory cytokine levels. It decreased EA levels as well as serum levels of sCD163 and sMR, but not zonulin, and both decreases in sCD163 and sMR showed positive correlations with EA decrease (ΔsCD163: Correlation coefficient (R) = 0.680, p = 0.023; ΔsMR: R = 0.613, p = 0.014, vs. ΔEA). Gut microbial analysis revealed that the richness and complexity of species were unchanged while the abundance of the Streptococcus genus was reduced after treatment with rifaximin. Collectively, rifaximin alleviated HE and endotoxemia with improved intestinal hyperpermeability in patients with decompensated cirrhosis, and this effect is partially involved in a gut microbial change.

18.
Dig Dis ; 38(4): 329-334, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31655803

RESUMO

AIMS: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). To increase platelet counts, lusutrombopag, a small-molecule, second-generation thrombopoietin receptor agonist, was developed in September 2015. Lusutrombopag is mainly used in patients with platelet counts <50,000/µL. However, its usefulness in patients with platelet counts ≥50,000/µL remains unknown. We studied the effectiveness of lusutrombopag administration in patients with platelet counts of ≥50,000/µL. METHODS: We evaluated 36 patients who received lusutrombopag for CLD. Changes in platelet counts were evaluated. A treatment response was defined as an increasing platelet count ≥20,000/µL from baseline after drug administration. The differences related to these changes between platelet counts ≥50,000 and <50,000/µL were evaluated. RESULTS: Of the patients, 25 had platelet counts ≥50,000/µL. The increase in platelet count and the date in which it reached a maximum did not significantly differ between the groups. The effectiveness of lusutrombopag did not significantly differ between the groups. In both groups, no adverse reaction was observed during lusutrombopag administration. CONCLUSION: In this study, we showed the effectiveness of lusutrombopag, which had no complications. This study is the first to report that the effectiveness of lusutrombopag was the same for patients with platelet counts ≥50,000/µL and <50,000/µL.


Assuntos
Cinamatos/uso terapêutico , Tiazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Contagem de Plaquetas , Complicações Pós-Operatórias/etiologia , Receptores de Trombopoetina/agonistas , Trombocitopenia/sangue , Fatores de Tempo , Resultado do Tratamento
19.
Cells ; 8(10)2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561561

RESUMO

Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Cirrose Hepática/tratamento farmacológico , Ácido Oleanólico/administração & dosagem , Pirimidinas/administração & dosagem , Receptores Acoplados a Proteínas G/metabolismo , Administração Oral , Animais , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Disbiose/tratamento farmacológico , Disbiose/genética , Fezes/microbiologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Masculino , Ácido Oleanólico/farmacologia , Pirimidinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/agonistas
20.
Hepatol Res ; 49(10): 1147-1161, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177586

RESUMO

AIM: Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. METHODS: Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro. RESULTS: Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-ß1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-ß1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC. CONCLUSIONS: Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.

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