RESUMO
BACKGROUND: Oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease (NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms (SNPs) in the regulatory region of genes encoding NADPH oxidase 4 (NOX4) and p22phox (CYBA) in NAFLD. METHODS: A total of 207 biopsy-proven NAFLD patients [simple steatosis (nâ¯=â¯27); nonalcoholic steatohepatitis (NASH) (nâ¯=â¯180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA (unregistered) and NOX4 (rs3017887) were determined by direct sequencing of PCR. RESULTS: Associations of CYBA-675 T/A with high-density lipoprotein (HDL) (TT vs TA vs AA; Pâ¯<â¯0.01) and triglycerides (TGL) (TT vs XA; Pâ¯<â¯0.01) were observed only in NASH patients. For polymorphisms in the NOX4 gene, NOX4 (rs3017887) CAâ¯+â¯AA genotypes was significant associated with alanine aminotransferase (ALT) (CAâ¯+â¯AA vs CC; Pâ¯=â¯0.02). However, there was no association of SNPs in the CYBA and NOX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus (66.9% vs 37.5%, Pâ¯<â¯0.01) and those who were more obese (32.2 vs 29.0â¯kg/m2, Pâ¯<â¯0.01). In addition, serum glucose and insulin levels increased significantly in the presence of NASH. CONCLUSIONS: There were associations between the presence of the allele A in the NOX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients.
Assuntos
Síndrome Metabólica/genética , NADPH Oxidase 4/genética , NADPH Oxidases/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Brasil/epidemiologia , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Cirrose Hepática/sangue , Cirrose Hepática/enzimologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/genética , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/enzimologia , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fenótipo , Fatores de RiscoRESUMO
AIM: To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal. METHODS: We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P < 0.05). RESULTS: In the Brazilian sample, NASH was significantly more frequent among the elderly patients with diabetes (NASH 56 ± 1.1 years old vs S. Steatosis 51 ± 1.5 years old, P = 3.7 x 10(-9)), dyslipidemia (NASH 63% vs S. Steatosis 37%, P = 0.009), higher fasting glucose levels (NASH 124 ± 5.2 vs S. Steatosis 106 ± 5.3, P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S. Steatosis groups. CONCLUSION: There was no difference between the genetic ancestry contribution among Brazilian and Portuguese individuals with NASH and S. Steatosis from each cohort.
RESUMO
S-Nitroso-N-acetylcysteine (SNAC) is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH) induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2), transforming growth factor ß-1 [TGFß-1], collagen-1α, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90) were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFß-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH.
Assuntos
Acetilcisteína/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Cirrose Hepática Experimental/prevenção & controle , Acetilcisteína/metabolismo , Acetilcisteína/uso terapêutico , Animais , Imuno-Histoquímica , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Ratos , Ratos Sprague-DawleyRESUMO
CONTEXT: Thyroid hormones may interfere with regulation of lipid and carbohydrate metabolism as well as with severity of nonalcoholic fatty liver disease (NAFLD), however results are still debated. OBJECTIVES: Retrospective evaluation of clinical and metabolic correlations between hypothyroidism and NAFLD was the target. METHODS: Clinical, biochemical and histological investigation of 103 NAFLD patients exhibiting drug-treated hypothyroidism was conducted. RESULTS: Steatosis was present in 32.0% of the population and nonalcoholic steatohepatitis in 68.0%. Females were the majority in both groups, with age of 50.0 ± 1.5 and 56.0 ± 1.1 years, respectively. Hypothyroidism was not rare (15.5%), and multivariate analysis confirmed positive correlation with this disease for insulin (r = 0.213, P = 0.03), glucose homeostasis index "HOMA" (r = 0.221, P = 0.02), aspartate aminotransferase (r = 0.234, P = 0.01) and triglycerides above 150 mg/dL (r = 0.233, P = 0.01). No association between hypothyroidism and steatohepatitis could be established. CONCLUSION: A link could be identified between hypothyroidism and markers of glucose and lipid homeostasis, but not with severity of NAFLD. The lack of correlation with liver biopsy requires further studies.
Assuntos
Aspartato Aminotransferases/sangue , Fígado Gorduroso/sangue , Glicolipídeos/sangue , Hipotireoidismo/sangue , Insulina/sangue , Triglicerídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Fígado Gorduroso/complicações , Feminino , Homeostase , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Estudos RetrospectivosRESUMO
CONTEXT: Thyroid hormones may interfere with regulation of lipid and carbohydrate metabolism as well as with severity of nonalcoholic fatty liver disease (NAFLD), however results are still debated. OBJECTIVES: Retrospective evaluation of clinical and metabolic correlations between hypothyroidism and NAFLD was the target. METHODS: Clinical, biochemical and histological investigation of 103 NAFLD patients exhibiting drug-treated hypothyroidism was conducted. RESULTS: Steatosis was present in 32.0 percent of the population and nonalcoholic steatohepatitis in 68.0 percent. Females were the majority in both groups, with age of 50.0 ± 1.5 and 56.0 ± 1.1 years, respectively. Hypothyroidism was not rare (15.5 percent), and multivariate analysis confirmed positive correlation with this disease for insulin (r = 0.213, P = 0.03), glucose homeostasis index "HOMA" (r = 0.221, P = 0.02), aspartate aminotransferase (r = 0.234, P = 0.01) and triglycerides above 150 mg/dL (r = 0.233, P = 0.01). No association between hypothyroidism and steatohepatitis could be established. CONCLUSION: A link could be identified between hypothyroidism and markers of glucose and lipid homeostasis, but not with severity of NAFLD. The lack of correlation with liver biopsy requires further studies.
CONTEXTO: Os hormônios tireoidianos podem interferir na regulação do metabolismo de lipídios e carboidratos e também na gravidade da doença hepática gordurosa não-alcoólica (DHGNA), porém os resultados ainda são debatidos. OBJETIVOS: Avaliar retrospectivamente correlações clínicas e metabólicas entre hipotireoidismo e DHGNA. MÉTODOS: Em 103 pacientes com DHGNA confirmada por biopsia e também hipotireoidismo recebendo tratamento, procedeu-se à investigação clínica, bioquímica e histológica. RESULTADOS: A esteatose foi observada em 32,0 por cento e a esteatohepatite não-alcoólica em 68,0 por cento da população. O sexo feminino foi mais frequente nas duas circunstâncias, com idade média de 50,0 ± 1,5 e 56,0 ± 1,1 anos, respectivamente. O hipotireoidismo não foi raro (15,5 por cento), sendo que na análise multivariada insulina (r = 0,213, P = 0,03), índice de homeostase glicídica HOMA (r = 0,221, P = 0,02), aspartato aminotransferase (r = 0,234, P = 0,01) e triglicerídeos acima de 150 mg/dL (r = 0,233, P = 0,01) foram correlacionados positivamente com hipotireoidismo. A associação entre hipotireoidismo e esteatohepatite não pôde ser estabelecida neste estudo. CONCLUSÃO: O hipotireoidismo vinculou-se à piora de alguns marcadores do metabolismo glicolipídico, porém não a lesões histológicas mais avançadas. A falta de correlação com a biopsia do fígado requer maiores estudos.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aspartato Aminotransferases/sangue , Fígado Gorduroso/sangue , Glicolipídeos/sangue , Hipotireoidismo/sangue , Insulina/sangue , Triglicerídeos/sangue , Biomarcadores/sangue , Fígado Gorduroso/complicações , Homeostase , Hipotireoidismo/complicações , Hipotireoidismo/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: Fatty liver disease is a problem in both bariatric patients and in patients with moderate obesity. Tumor necrosis factor (TNF)-alpha has been frequently measured in nonalcoholic steatohepatitis (NASH) with or without diabetes, but less is known about interleukin (IL)-6 and IL-10. METHODS: Moderately obese patients (n = 80) with histologically proven steatosis (n = 29) and NASH (n = 51) were recruited. Serum levels of cytokines were documented along with clinical information. The aim was to identify the correlates of such biomolecules in a stable population. RESULTS: Diabetes tended to be more associated with NASH (52.5% instead of 41.4%, P = 0.015), with no difference of age, gender, or body mass index regarding steatosis. For the entire population, cytokine changes were not significant, including TNF-alpha and IL-6. In diabetics only, all markers tended to diminish with NASH, especially IL-10 (P = 0.000). IL-10 correlated with homeostatic model assessment index (P = 0.000) and other variables of glucose homeostasis in diabetes, thus representing a major marker of the disease. CONCLUSIONS: (1) Generally inconsistent changes in pro- and anti-inflammatory cytokines occurred when NASH was globally compared to steatosis. (2) In contrast, downregulation of IL-6 and IL-10 was perceived in diabetics with NASH. (3) Arterial hypertension did not play a role in these circumstances. (4) IL-10 maintained strong correlations with glucose metabolism indices. (5) TNF-alpha could not be incriminated for progressive liver damage, as values failed to increase in NASH. (6) Investigations of IL-10 and other counterregulatory cytokines are lacking in this context and deserve further studies.