Dietary restriction, caloric value and the accumulation of hepatic fat

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Avaliação clínica, laboratorial e dos marcadores bioquímicos do estresse oxidativo hepatocelular em ratos diabéticos induzidos pela aloxana

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Efeito da fibra dietética e do exercício físico resistido na doença hepática gordurosa

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação dos marcadores clínicos e inflamatórios da doença hepática gordurosa não alcoólica em mulheres na pós-menopausa com síndrome metabólica

Pós-graduação em Ginecologia, Obstetrícia e Mastologia - FMB

Estudo da inflamação e da autoimunidade na doença hepática gordurosa não alcoólica

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

Lipidose hepática felina

Feline hepatic lipidosis or fatty liver disease is a cholestatic syndrome that affects domestic cats and is characterized by excess fat accumulation in the liver of cats. Symptoms commonly seen with this syndrome are anorexia, weight loss, lethargy, vomiting, jaundice, and occasionally behavioral or neurologic signs such as excessive drooling, blindness, coma, and seizures. The diagnosis is based on the patient history, clinical examination, complementary examination, and the definitive diagnosis is obtained by cytology and/or histopathology of hepatic tissue. In serum biochemistry, the main findings include increased serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate amino transferase (AST) and bilirubin. The gamma glutamyl transferase (GGT) is normal or slightly increased. The cornerstone of therapy is aggressive feeding to supply the cat full caloric requirements. Without aggressive nutritional support and intensive monitoring the fatty liver disease can be fatal

Influência da vitamina D sérica na adiponectina, visfatina e resistina nas alterações histológicas no fígado de pacientes com doença hepática gordurosa não alcoólica

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Relation of Uric Acid to Serum Levels of High-Sensitivity C-Reactive Protein, Triglycerides, and High-Density Lipoprotein Cholesterol and to Hepatic Steatosis

Increased uric acid (UA) is strongly linked to cardiovascular disease. However, the independent role of UA is still debated because it is associated with several cardiovascular risk factors including obesity and metabolic syndrome. This study assessed the association of UA with increased high-sensitivity C-reactive protein (hs-CRP), increased ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL), sonographically detected hepatic steatosis, and their clustering in the presence and absence of obesity and metabolic syndrome. We evaluated 3,518 employed subjects without clinical cardiovascular disease from November 2008 through July 2010. Prevalence of tis-CRP >= 3 mg/L was 19%, that of TG/HDL >= 3 was 44%, and that of hepatic steatosis was 43%. In multivariable logistic regression after adjusting for traditional cardiovascular risk factors and confounders, highest versus lowest UA quartile was associated with hs-CRP >= 3 mg/L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.01 to 2.28, p = 0.04), TG/HDL >= 3 (OR 3.29, 95% CI 2.36 to 4.60, p <0.001), and hepatic steatosis (OR 3.10, 95% CI 2.22 to 4.32, p <0.001) independently of obesity and metabolic syndrome. Association of UA with hs-CRP >= 3 mg/L became nonsignificant in analyses stratified by obesity. Ascending UA quartiles compared to the lowest UA quartile demonstrated a graded increase in the odds of having 2 or 3 of these risk conditions and a successive decrease in the odds of having none. In conclusion, high UA levels were associated with increased TG/HDL and hepatic steatosis independently of metabolic syndrome and obesity and with increased hs-CRP independently of metabolic syndrome. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1787-1792)

Altered Glucose Homeostasis and Hepatic Function in Obese Mice Deficient for Both Kinin Receptor Genes

The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.

Il "Progetto Bagnacavallo": prevalenza dell'ipertransaminasemia e NAFLD nella popolazione generale

Nel corso degli ultimi due decenni in particolare si è andata evidenziando a livello epatologico una entità definita oggi Non-alcoholic Fatty Liver Disease (NAFLD) che si è andata ad affiancare alle cause in precedenza conosciute, fino a risultare, attraverso il succedersi di riscontri scientifici, la causa prevalente di epatopatia, in particolare nei paesi occidentali e industrializzati. Negli stessi anni un'altra problematica clinica complessa che va sotto il nome di Sindrome Metabolica si è andata via via delineando attraverso le sue molteplici correlazioni con quelle che sono le cause di morbidità e mortalità prevalenti nella nostra realtà, dal diabete alla patologia cardiovascolare e non ultima alla NAFLD stessa. Scopo dello Studio in oggetto a questa tesi era proprio di rivalutare nel territorio italiano la prevalenza di epatopatia in particolare correlabile alla NAFLD e la sua associazione con la Sindrome Metabolica.

Il sistema degli endocannabinoidi nella cirrosi epatica complicata da infezione batterica: studio nell’uomo ed in un modello sperimentale animale

Gli endocannabinoidi (EC) sono una classe di composti che mimano gli effetti del Δ9-tetraidrocannabinolo. Essi comprendono l’anandamide (AEA) ed il 2-arachidonoilglicerolo (2-AG), molecole che interagiscono preferenzialmente con due specifici recettori, il CB1 ed il CB2. Più recente è la scoperta di due molecole EC simili, il palmitoiletanolamide (PEA) e l’oleiletanolamide (OEA), che tuttavia agiscono legando recettori diversi tra cui il PPARα ed il TRVP1. Studi sperimentali dimostrano che il sistema degli EC è attivato in corso di cirrosi epatica ed è coinvolto nel processo fibrogenico e nella patogenesi delle alterazioni emodinamiche tipiche della malattia. Esso partecipa alla patogenesi di alcune delle maggiori complicanze della cirrosi quali ascite, encefalopatia, cardiomiopatia ed infezioni batteriche. Scopo del presente studio è stato quello di studiare il ruolo degli EC nella patogenesi delle infezioni batteriche in corso di cirrosi. A tale scopo sono stati eseguiti un protocollo clinico ed uno sperimentale. Nel protocollo sperimentale la cirrosi è stata indotta mediante somministrazione di CCl4 per via inalatoria a ratti maschi Wistar. In tale protocollo i livelli circolanti di tutti gli EC sono risultati significativamente aumentati a seguito della somministrazione di LPS. La somministrazione dell’antagonista del recettore CB1, Rimonabant, inoltre, è stata efficace nel ridurre del 50% la mortalità a 24 ore dei ratti trattati col farmaco rispetto ai ratti trattati col solo LPS. Parallelamente il Rimonabant ha determinato una riduzione dell’espressione genica di molecole pro-infiammatorie e sostanze vasoattive. Lo studio clinico, condotto su 156 pazienti, ha confermato l’attivazione del sistema degli EC in corso di cirrosi epatica. Inoltre è stata identificata una forte correlazione tra il PEA e l’OEA e l’emodinamica sistemica ed una associazione con alcune delle maggiori complicanze. L’analisi statistica ha inoltre individuato l’OEA quale predittore indipendente di insufficenza renale e di sopravvivenza globale.

Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN

The metabolic disorders that predispose patients to NASH (non-alcoholic steatohepatitis) include insulin resistance and obesity. Repeated hypoxic events, such as occur in obstructive sleep apnoea syndrome, have been designated as a risk factor in the progression of liver disease in such patients, but the mechanism is unclear, in particular the role of hypoxia. Therefore we studied the influence of hypoxia on the development and progression of steatohepatitis in an experimental mouse model. Mice with a hepatocellular-specific deficiency in the Pten (phosphatase and tensin homologue deleted on chromosome 10) gene, a tumour suppressor, were exposed to a 10% O2 (hypoxic) or 21% O2 (control) atmosphere for 7 days. Haematocrit, AST (aspartate aminotransferase), glucose, triacylglycerols (triglycerides) and insulin tolerance were measured in blood. Histological lesions were quantified. Expression of genes involved in lipogenesis and mitochondrial beta-oxidation, as well as FOXO1 (forkhead box O1), hepcidin and CYP2E1 (cytochrome P450 2E1), were analysed by quantitative PCR. In the animals exposed to hypoxia, the haematocrit increased (60+/-3% compared with 50+/-2% in controls; P<0.01) and the ratio of liver weight/body weight increased (5.4+/-0.2% compared with 4.7+/-0.3% in the controls; P<0.01). Furthermore, in animals exposed to hypoxia, steatosis was more pronounced (P<0.01), and the NAS [NAFLD (non-alcoholic fatty liver disease) activity score] (8.3+/-2.4 compared with 2.3+/-10.7 in controls; P<0.01), serum AST, triacylglycerols and glucose were higher. Insulin sensitivity decreased in mice exposed to hypoxia relative to controls. The expression of the lipogenic genes SREBP-1c (sterol-regulatory-element-binding protein-1c), PPAR-gamma (peroxisome-proliferator-activated receptor-gamma), ACC1 (acetyl-CoA carboxylase 1) and ACC2 (acetyl-CoA carboxylase 2) increased significantly in mice exposed to hypoxia, whereas mitochondria beta-oxidation genes [PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and CPT-1 (carnitine palmitoyltransferase-1)] decreased significantly. In conclusion, the findings of the present study demonstrate that hypoxia alone aggravates and accelerates the progression of NASH by up-regulating the expression of lipogenic genes, by down-regulating genes involved in lipid metabolism and by decreasing insulin sensitivity.

[Non-alcoholic steatohepatitis - from NAFLD to MAFLD]

Non-alcoholic steatohepatitis (NASH) as one entity of non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and accompanies the rise in the prevalence of obesity, diabetes mellitus, hypertension and hyperlipidemia in the western world. It is not known why some patients progress in the disease and develop inflammation in the liver, whereas others remain in the stage of simple steatosis, which generally has a benign course. However, NASH can progress to fibrosis and cirrhosis as well as hepatocellular carcinoma. Therefore, it is important to determine the stage of the disease in patients presenting with the metabolic syndrome and abnormal liver function tests, suggesting NAFLD. Liver biopsy is the only tool that allows for reliable detection, grading and staging of liver disease. The main strategies in the treatment of NASH are correction of risk factors (lifestyle modifications, insuline sensitizer) and anti-oxidants (ursodeoxycholic acid, vitamin E) which both have been shown to improve liver histology as well as liver enzymes. Patients wih alcoholic fatty liver disease (AFLD) present the same liver histology and often also metabolic alterations similar to metabolic syndrome. Therefore, MAFLD (metabolic syndrome-associated fatty liver disease) might describe both patient populations more accurately and also describes the pathophysiological characteristics.

[In Process Citation]

Elevated transaminases in asymptomatic patients can be detected in more than 5 % of the investigations. If there are no obvious reasons, the finding should be confirmed within the next 3 months. Frequent causes are non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol, hepatitis B or C, hemochromatosis and drugs or toxins. Rarer causes are autoimmune hepatitis, M. Wilson and α1-antitrypsine deficiency. There are also non-hepatic causes such as celiac disease or hemolysis and myopathies in the case of an exclusive increase of ASAT. I recommend a two-step investigational procedure; the more frequent causes are examined first before the rare causes are studied. The value of the proposed investigations is discussed.

Magic angle spinning magnetic resonance: a novel method opening up translational research into NAFLD?

NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis) are of increasing importance, both in connection with insulin resistance and with the development of liver cirrhosis. Histological samples are still the 'gold standard' for diagnosis; however, because of the risks of a liver biopsy, non-invasive methods are needed. MAS (magic angle spinning) is a special type of NMR which allows characterization of intact excised tissue without need for additional extraction steps. Because clinical MRI (magnetic resonance imaging) and MRS (magnetic resonance spectroscopy) are based on the same physical principle as NMR, translational research is feasible from excised tissue to non-invasive examinations in humans. In the present issue of Clinical Science, Cobbold and co-workers report a study in three animal strains suffering from different degrees of NAFLD showing that MAS results are able to distinguish controls, fatty infiltration and steatohepatitis in cohorts. In vivo MRS methods in humans are not obtainable at the same spectral resolution; however, know-how from MAS studies may help to identify characteristic changes in crowded regions of the magnetic resonance spectrum.