RESUMO
We discuss the case of a rare and often unrecognized neurologic syndrome, called Acquired Hepatocerebral Degeneration (AHD), observed in patients with advanced liver disease and portosystemic shunts. The clinical manifestations can be very heterogeneous and in our case included a combination of cerebellar and extrapyramidal signs, arisen in a period of few days. Brain Magnetic Resonance Imaging (MRI) showed, in T1-weighted images, diffuse bilateral hyper intensities in basal ganglia and biemispheric brain and cerebellar cortices, resembling paramagnetic deposits. No other neurological impairments, like stroke, infection or neoplasia, were found. It was excluded an episode of acute hepatic encephalopathy. We also ruled out Wilsonian degeneration, iron overload and autoimmune encephalitis and we lastly found high manganese levels as the possible cause of the brain paramagnetic deposits. Even though either serum Mn determination or its accumulation in the brain are not specific for AHD, however the chronic and progressively worsening of the neurological manifestations advocated a degenerative condition, possibly AHD. We finally opted for the early restoration of liver function by OLT, and we observed complete clinical symptoms' resolution and partial MRI reversal after a follow up of 6 months.
Assuntos
Encéfalo/patologia , Degeneração Hepatolenticular/diagnóstico por imagem , Degeneração Hepatolenticular/patologia , Cirrose Hepática/complicações , Adulto , Doença Crônica , Feminino , Seguimentos , Degeneração Hepatolenticular/etiologia , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND AND AIMS: Abdominal obesity and hepatic steatosis are ectopic fat depots associated with Metabolic Syndrome (MetS). Epicardial Fat Thickness (EFT) is a newly discovered one, increasing with obesity, insulin resistance and MetS. Therefore we studied whether different ectopic fat markers, and EFT in particular, are associated with MetS and markers of subclinical cardiovascular disease. METHODS AND RESULTS: 868 subjects from the PLIC Study were included, EFT, aortic calcifications, carotid Intima-Media Thickness (c-IMT) and echocardiographic parameters were determined by ultrasound; extra-cardiac atherosclerotic lesions were defined in presence of plaques at both carotid and aortic levels. Hepatic steatosis degrees were defined according to a scoring system. Abdominal adiposity was determined using Dual X-ray Absorbimetry (DEXA). Independently from age, women showed higher EFT versus men (4.5 (0.20-9.00) mm vs 4.00 (0.10-8.00) mm, p = 0.013); EFT was thicker in post-menopausal women (independently from hormone-replacement therapy). EFT, liver steatosis and abdominal adiposity increased with MetS (p < 0.001). EFT was the only ectopic fat marker associated with cardiac dysfunction (OR = 1.340 [1.088-1.651 95% C.I., p = 0.006); liver steatosis and EFT were associated with extra-cardiac plaques (OR = 2.529 [1.328-4.819] 95% C.I., p < 0.001 and OR = 1.195 [1.008-1.299] 95% C.I., p = 0.042; respectively). On top of cardiovascular risk factors, only EFT improved the discrimination of subjects with cardiac dysfunction and atherosclerotic plaques. CONCLUSIONS: EFT is associated with left ventricular dysfunction and subclinical atherosclerosis. Our data suggest that EFT may represent an additional tool for the stratification of cardiovascular risk.
Assuntos
Adiposidade , Doenças da Aorta/complicações , Aterosclerose/etiologia , Doenças das Artérias Carótidas/etiologia , Fígado Gorduroso/complicações , Síndrome Metabólica/complicações , Obesidade/complicações , Calcificação Vascular/etiologia , Absorciometria de Fóton , Tecido Adiposo , Idoso , Doenças da Aorta/diagnóstico por imagem , Doenças Assintomáticas , Aterosclerose/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Distribuição de Qui-Quadrado , Ecocardiografia Doppler em Cores , Fígado Gorduroso/diagnóstico por imagem , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/diagnóstico , Razão de Chances , Pericárdio , Placa Aterosclerótica , Valor Preditivo dos Testes , Fatores de Risco , Fatores Sexuais , Calcificação Vascular/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologiaRESUMO
AIMS: To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. METHODS AND RESULTS: Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9⯱â¯0.4â¯vs 0.7⯱â¯0.4; p<0.01; IVC end-expiratory diameter: 21.6⯱â¯5.1â¯mm vs 20±5.5â¯mm, p<0.01; IVC collapsibility index 24.4⯱â¯17.4% vs 30.9⯱â¯21.1% p<0.01) and higher Nt-proBNP values (8010â¯vs 3900â¯ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4⯱â¯4â¯vs 0.3⯱â¯0.4; pâ¯=â¯0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, pâ¯=â¯0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. CONCLUSIONS: Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.
Assuntos
Insuficiência Cardíaca , Diuréticos/uso terapêutico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Prognóstico , Estudos Prospectivos , Volume SistólicoRESUMO
Recently, genome-wide association studies in patients affected by HCV infection have identified a strong association between sustained virological response to peg-interferon/ribavirin and spontaneous viral clearance and common single nucleotide polymorphisms (SNPs) near the IL28B gene, encoding for interferon-lambda-3. Thus, it is anticipated that IL28B genotype determination will be integrated in clinical practice to guide treatment decisions. Here, we describe a simple tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) for the evaluation of the rs12979860 C>T IL28B SNP, for which strong evidence of association with clinical outcomes has been collected in subjects of European descent. Valid genotypic data were obtained for over 99% of subjects analysed, and T-ARMS-PCR procedures were validated by the analysis of DNA samples of 164 patients with chronic HCV infection. In conclusion, this method allows rapid, reproducible, inexpensive and accurate detection of rs12979860 polymorphism without need of any special equipment and is also suitable for evaluation of a low number of samples on a routine basis.
Assuntos
Testes Genéticos/métodos , Hepatite C Crônica/genética , Interleucinas/genética , Reação em Cadeia da Polimerase/métodos , Adulto , Idoso , Alelos , Antivirais/uso terapêutico , Feminino , Genótipo , Hepacivirus/patogenicidade , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferons , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ribavirina/uso terapêutico , Resultado do Tratamento , População Branca/genéticaRESUMO
BACKGROUND AND AIMS: Increased ferritin and body iron stores are frequently observed in nonalcoholic fatty liver disease (NAFLD), associated with heightened susceptibility to vascular damage. Conflicting data have been reported on the role of iron in atherosclerosis, with recent data suggesting that excess iron induces vascular damage by increasing levels of the hormone hepcidin, which would determine iron trapping into macrophages, oxidative stress, and promotion of transformation into foam cells. Aim of this study was to investigate the relationship between iron status and cardiovascular damage in NAFLD. METHODS AND RESULTS: Vascular damage was evaluated by common carotid arteries intima-media thickness (CC-IMT) measurement and plaque detection by ecocolor-doppler ultrasonography in 506 patients with clinical and ultrasonographic diagnosis of NAFLD, hemochromatosis gene (HFE) mutations by restriction analysis in 342 patients. Serum hepcidin-25 was measured by time-of-flight mass spectrometry in 143 patients. At multivariate analysis CC-IMT was associated with systolic blood pressure, glucose, LDL cholesterol, abdominal circumference, age, and ferritin (p=0.048). Carotid plaques were independently associated with age, ferritin, glucose, and hypertension. Ferritin reflected iron stores and metabolic syndrome components, but not inflammation or liver damage. Hyperferritinemia was associated with increased vascular damage only in patients with HFE genotypes associated with hepcidin upregulation by iron stores (p<0.0001), and serum hepcidin-25 was independently associated with carotid plaques (p=0.05). CONCLUSION: Ferritin levels, reflecting iron stores, are independent predictors of vascular damage in NAFLD. The mechanism may involve upregulation of hepcidin by increased iron stores in patients not carrying HFE mutations, and iron compartmentalization into macrophages.
Assuntos
Fígado Gorduroso/patologia , Ferritinas/sangue , Doenças Vasculares/patologia , Adulto , Idoso , Peptídeos Catiônicos Antimicrobianos/sangue , Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Feminino , Genótipo , Hemocromatose/sangue , Hemocromatose/genética , Hemocromatose/patologia , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/patologia , Ferro/sangue , Itália , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Hepatopatia Gordurosa não Alcoólica , Adulto JovemRESUMO
BACKGROUND/AIMS: The aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance. PATIENTS AND METHODS: 702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients. RESULTS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of approximately 70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD. CONCLUSIONS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.
Assuntos
Fígado Gorduroso/genética , Proteínas Substratos do Receptor de Insulina/genética , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Receptor de Insulina/metabolismo , Adulto , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Transdução de Sinais/genéticaRESUMO
The fatty acid transport protein 5 (FATP5) is exclusively expressed in the liver and is involved in hepatic lipid and bile metabolism. We investigated whether a variation in the FATP5 promoter (rs56225452) is associated with hepatic steatosis and further features of the metabolic syndrome. A total of 716 male subjects from the Metabolic Intervention Cohort Kiel (MICK) and 103 male subjects with histologically proved nonalcoholic fatty liver disease (NAFLD) were genotyped for this FATP5 polymorphism rs56225452 and phenotyped for features of the metabolic syndrome. In the MICK cohort, ALT activities, postprandial insulin, and triglyceride concentrations were higher in subjects carrying the rare A-allele compared to GG homozygotes. Accordingly, the insulin sensitivity index determined after a mixed meal and standardized glucose load was lower in A-allele carriers. NAFLD cases carrying allele A were presented with also higher ALT activities. In NAFLD subjects, the association of BMI with the degree of steatosis and glucose concentration differed across FATP5 promoter polymorphism. The FATP5 promoter polymorphism rs56225452 is associated with higher ALT activity, insulin resistance, and dyslipidemia in the general population. The impact of the BMI on the severity of steatosis in NAFLD cases seems to depend on the FATP5 polymorphism.
Assuntos
Proteínas de Transporte de Ácido Graxo/genética , Fígado Gorduroso/genética , Fígado/metabolismo , Síndrome Metabólica/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Idoso , Índice de Massa Corporal , Proteínas de Transporte de Ácido Graxo/metabolismo , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Especificidade de Órgãos , Estudos Prospectivos , População Branca/genéticaRESUMO
SUMMARY: In 87 patients with hereditary hemochromatosis, osteoporosis was detected in 25%, and osteopenia in 41%. Bone mineral density was independently associated with BMI, ALP levels, hypogonadism/menopause, and the amount of iron removed to reach depletion, but not with cirrhosis. Osteoporosis is influenced by iron overload in hemochromatosis. INTRODUCTION: To analyze prevalence, clinical characteristics and genetic background associated with osteoporosis in a retrospective study in Italian patients with hereditary hemochromatosis (HHC). METHODS: In 87 consecutive patients with HHC, bone mineral density was systematically evaluated by dual energy x-ray absorptiometry of the lumbar spine (n = 87) and femoral neck (n = 66). RESULTS: Osteoporosis was detected in 22 (25.3%), and osteopenia in 36 (41.4%) patients. Mean Z scores were -0.92 +/- 1.42 at lumbar spine and -0.35 +/- 1.41 at femoral neck. Lumbar spine T-score was independently associated with total ALP (p = 0.002), hypogonadism/menopause (p = 0.026), and iron overload (p = 0.033 for ferritin and p = 0.017 for iron removed). We observed a borderline significance for BMI (p = 0.069) and smoking status (p = 0.086). Lumbar spine osteoporosis was independently associated with lower BMI (OR 0.73, 95% CI 0.54-0.94), total ALP (OR 1.17, 95% CI 1-1.39 per 10 unit increase) and the amount of iron removed (OR 1.53, 95% CI 1-2.5 per 5 g increase). HFE genotypes did not differ between patients with and without osteoporosis. CONCLUSIONS: Osteoporosis is observed in a quarter of unselected patients with HHC, independently of the genetic background, and is associated with ALP, hypogonadism, body weight, and severity of iron overload.
Assuntos
Hemocromatose/complicações , Osteoporose/etiologia , Absorciometria de Fóton , Adulto , Fosfatase Alcalina/metabolismo , Índice de Massa Corporal , Densidade Óssea , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/fisiopatologia , Feminino , Colo do Fêmur/fisiopatologia , Hemocromatose/fisiopatologia , Humanos , Vértebras Lombares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Osteoporose/fisiopatologia , Estudos RetrospectivosRESUMO
BACKGROUND: Preliminary clinical and experimental results suggest that iron can modify hepatocytes' insulin sensitivity by interfering with insulin receptor and intracellular insulin signalling. AIM: To evaluate in vivo the influence of iron on insulin resistance and insulin release in patients with non-alcoholic fatty liver disease and in vitro the interaction between iron and insulin sensitivity by analysing the effect of iron manipulation on insulin receptor expression in hepatoblastoma HepG2 cell line. RESULTS: Insulin resistance evaluated by homeostatis model assessment (HOMA)-insulin resistance significantly decreased after diet, and a further reduction was observed after phlebotomies. Iron depletion by desferrioxamine increased by twofold the 125I-insulin-specific binding, whereas iron addition reduced insulin binding, similarly to cells exposed to high glucose concentration. CONCLUSION: Iron status affects insulin sensitivity by modulating the transcription and membrane expression/affinity of insulin receptor expression in hepatocytes and influencing insulin-dependent gene expression suggesting that increased insulin clearance and decreased insulin resistance may contribute to the positive effect of iron depletion in patients with non-alcoholic fatty liver disease.
Assuntos
Fígado Gorduroso/metabolismo , Resistência à Insulina , Ferro/metabolismo , Linhagem Celular Tumoral , Desferroxamina/metabolismo , Dieta , Ingestão de Energia , Feminino , Expressão Gênica , Glucoquinase/análise , Humanos , Insulina/metabolismo , Ferro/administração & dosagem , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Receptor de Insulina/metabolismoRESUMO
The A16V mitochondrial targeting sequence polymorphism influences the antioxidant activity of MnSOD, an enzyme involved in neutralising iron induced oxidative stress. Patients with hereditary haemochromatosis develop parenchymal iron overload, which may lead to cirrhosis, diabetes, hypogonadism, and heart disease. The objective of this study was to determine in patients with haemochromatosis whether the presence of the Val MnSOD allele, associated with reduced enzymatic activity, affects tissue damage, and in particular heart disease, as MnSOD knockout mice develop lethal cardiomyopathy. We studied 217 consecutive unrelated probands with haemochromatosis, and 212 healthy controls. MnSOD polymorphism was evaluated by restriction analysis. The frequency distribution of the polymorphism did not differ between patients and controls. Patients carrying the Val allele had higher prevalence of cardiomyopathy (A/A 4%, A/V 11%, V/V 30%, p = 0.0006) but not of cirrhosis, diabetes, or hypogonadism, independently of age, sex, alcohol misuse, diabetes, and iron overload (odds ratio 10.1 for V/V, p = 0.006). The frequency of the Val allele was higher in patients with cardiomyopathy (0.67 v 0.45, p = 0.003). The association was significant in both C282Y+/+ (p = 0.02), and in non-C282Y+/+ patients (p = 0.003), and for both dilated (p = 0.01) and non-dilated stage (p = 0.04) cardiomyopathy, but not for ischaemic heart disease. In patients with hereditary haemochromatosis, the MnSOD genotype affects the risk of cardiomyopathy related to iron overload and possibly to other known and unknown risk factors and could represent an iron toxicity modifier gene.
Assuntos
Cardiomiopatias/enzimologia , Hemocromatose/enzimologia , Polimorfismo Genético , Superóxido Dismutase/genética , Cardiomiopatias/complicações , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Hemocromatose/complicações , Hemocromatose/genética , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoAssuntos
Pesquisa Biomédica/organização & administração , Pesquisa Biomédica/normas , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Centros Médicos Acadêmicos , Betacoronavirus , Bancos de Espécimes Biológicos/normas , Bancos de Espécimes Biológicos/estatística & dados numéricos , Pesquisa Biomédica/estatística & dados numéricos , COVID-19 , Humanos , Comunicação Interdisciplinar , Itália/epidemiologia , Pandemias , Sistema de Registros/normas , Sistema de Registros/estatística & dados numéricos , SARS-CoV-2RESUMO
To address the potential role that tumor necrosis factor-alpha (TNF-alpha) might play in modulation of insulin resistance in healthy, nondiabetic individuals, we compared plasma TNF-alpha and soluble TNF-alpha receptor 2 (sTNF-R2) concentrations, as well as TNF-alpha polymorphisms, in 94 healthy individuals, stratified into insulin-resistant (IR) and insulin-sensitive (IS) groups based on their plasma insulin concentrations 120 minutes after oral glucose on 2 occasions (1993 and 2000). The IR group (n = 50; 29 men and 21 women) was in the upper quartile and the IS group (n = 44; 24 men and 20 women) in the lowest quartile of the distribution of post-glucose challenge insulin concentrations in a large unselected population (>50 v <23 microU/mL). The IR group had significantly higher values for body mass index, waist-to-hip girth, fasting and post-glucose challenge insulin concentrations, and fasting triglyceride concentrations, and lower high-density lipoprotein cholesterol concentrations as compared to the IS group. Despite the fact that they were relatively more obese, and insulin-resistant, plasma concentrations of TNF-alpha were similar in the IR (1.6 +/- 0.6 pg/mL) and IS (1.7 +/- 0.6 pg/mL) groups, as were the concentrations (5.4 +/- 1.4 v 5.8 +/- 2.0 pg/mL) of sTNF-R2. Furthermore, TNF-alpha polymorphisms (detected by polymerase chain reaction [PCR]) were similar in the 2 groups, with essentially identical allelic frequencies of the 238 (10.3% v 9.4%) and 308 polymorphisms (17.9% v 18.7%). In conclusion, plasma TNF-alpha and sTNF-R2 concentrations, as well as TNF-alpha gene polymorphisms, were not different in healthy volunteers stratified into IR and IS groups on the basis of their plasma insulin response to an oral glucose challenge. Given these data, it does not appear that differences in TNF-alpha activity contribute to the marked variations in insulin action that occur in healthy individuals.
Assuntos
Resistência à Insulina/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Idoso , Glicemia/metabolismo , DNA/biossíntese , DNA/genética , DNA/isolamento & purificação , Jejum/fisiologia , Feminino , Glucose/farmacologia , Hemodinâmica/fisiologia , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: To define whether there is any relation between the iron status of patients with hepatitis C virus (HCV) chronic liver disease and their response to interferon therapy. DESIGN: To evaluate the long-term response to 1 year of interferon therapy with addition of phlebotomies after 3 months of treatment if at that time alanine aminotransferase (ALT) had not normalized in a group of patients with HCV-positive chronic liver disease whose iron status had been characterized. SETTING: A northern Italian hospital. PARTICIPANTS: Fifty-eight anti-HCV-positive patients (four HCV-RNA negative) with biopsy proven chronic hepatitis and no evidence of iron overload as indicated by normal transferrin saturation at the time of enrollment in the study. INTERVENTION: Three times a week intramuscular injection of alpha interferon 3 MU for 1 year with addition of phlebotomies (350 ml/week) till iron depletion if after 3 months of interferon therapy ALT had not normalized. RESULTS: A long-term response was observed in 19 of the 52 patients who completed the treatment, four HCV-RNA negative and 15 positive. The four RNA-negative and seven of the 15 RNA-positive long-term responders had been treated with interferon alone, and the other eight also with phlebotomies. At univariate analysis only HCV genotype, gamma-glutamyltranspeptidase and liver iron concentration were significantly associated with response whereas sinusoidal iron deposition was of borderline significance. No association was found with sex, age, duration of disease, histology, Knodell score, transferrin saturation %, serum ferritin, hepatocytic iron score, and portal iron score. HCV-RNA serum levels, measured in 29 patients, did not correlate with response. At multivariate analysis liver iron concentration was still significant and one unit reduction of liver iron concentration (natural logarithm transformed) was associated with 2.95 odds ratio of response. CONCLUSION: These results indicate that iron in the liver is more closely related to response to interferon than the other variables considered, including HCV characteristics.
Assuntos
Antivirais/uso terapêutico , Hepatite C/metabolismo , Interferon-alfa/uso terapêutico , Ferro/metabolismo , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Doença Crônica , Ensaio de Imunoadsorção Enzimática , Feminino , Ferritinas/sangue , Seguimentos , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C/patologia , Hepatite C/terapia , Anticorpos Anti-Hepatite C/análise , Humanos , Injeções Intramusculares , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Estudos Retrospectivos , Transferrina/metabolismo , gama-Glutamiltransferase/metabolismoRESUMO
OBJECTIVE: To determine whether alpha 1-antitrypsin deficiency is involved in the pathogenesis of chronic liver disease in patients with porphyria cutanea tarda and in their recently described high prevalence of hepatitis C virus infection. DESIGN: Consecutive patients diagnosed as having porphyria cutanea tarda and chronic liver disease. SETTING: A northern Italian hospital. METHODS: alpha 1-antitrypsin phenotypes were characterized by isoelectric focusing and the results confirmed by DNA analysis in 63 Italian patients with porphyria cutanea tarda. RESULTS: alpha 1-antitrypsin phenotypes different from the normal one were found in 13% of the patients. This prevalence did not differ from that in control subjects (9%). Clinical characteristics of patients with porphyria cutanea tarda with normal or altered alpha 1-antitrypsin phenotype, including age of presentation of the disease, prevalence of hepatitis C virus infection, liver histology, prevalence of iron overload and hepatocellular carcinoma occurrence, did not differ significantly. CONCLUSION: alpha 1-antitrypsin does not seem to play a role in the pathogenesis of chronic liver disease and hepatitis C virus infection in patients with porphyria cutanea tarda. Patients in whom the two defects coexist do not have a more severe disease.
Assuntos
Porfiria Cutânea Tardia/etiologia , Deficiência de alfa 1-Antitripsina , Adulto , Idoso , Feminino , Hepatite C/epidemiologia , Humanos , Sobrecarga de Ferro/epidemiologia , Fígado/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Fenótipo , Porfiria Cutânea Tardia/epidemiologia , Porfiria Cutânea Tardia/genética , PrevalênciaRESUMO
Ferritin receptors are present on the membranes of many normal and malignant cells. The binding specificity of these receptors for H and L subunits was examined using recombinant human ferritin homopolymers. At least two different types of ferritin receptors were found, one derived from normal rat, pig, and human liver which shows similar binding of H- and L-ferritin. The second receptor type, specific for the H-chain ferritin, has been identified on membranes of hepatic and other transformed cells, and of normal lymphoblasts and erythroid precursors. These two receptor types may have different metabolic functions: the hepatic receptor acting as a scavenger for circulating ferritin and possibly for iron exchange between hepatocytes and macrophages; the H-ferritin receptor having a regulatory role which is not directly related to iron metabolism. The expression of the H-ferritin receptor is closely related to the activation and proliferation state of the cells. Addition of H-ferritin to the culture medium of cells expressing the H-ferritin receptor resulted in inhibition of cell proliferation and of colony formation.
Assuntos
Carcinoma Hepatocelular/metabolismo , Eritrócitos/metabolismo , Proteínas de Ligação ao Ferro , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Linfócitos/metabolismo , Receptores de Superfície Celular/fisiologia , Animais , Divisão Celular , Linhagem Celular Transformada , Membrana Celular/metabolismo , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Ratos , Proteínas Recombinantes/metabolismo , Células Tumorais CultivadasRESUMO
BACKGROUND: A non-negligible percentage of patients with non-alcoholic fatty liver disease, a leading cause of hepatic progressive disorder related to insulin resistance, have no metabolic risk factors, and abnormal intestinal permeability has been suggested to be involved in the pathogenesis of the liver damage. Coeliac disease, a curable disorder characterised by inflammatory mucosal damage, may show hepatic histological features similar to steatohepatitis. Conflicting data have been reported on the prevalence of coeliac disease in non-alcoholic steatohepatitis. AIM: To search for coeliac disease in a series of patients with non-alcoholic fatty liver disease by screening with anti-tissue transglutaminase and anti-endomysium antibodies. PATIENTS AND METHODS: Fifty-nine consecutive patients with hypertransaminasemia and non-alcoholic fatty liver disease, 38 (64%) with steatohepatitis. Anti-endomysium antibodies were assayed by indirect immunofluorescence, IgA anti-tissue transglutaminase by ELISA. Patients who tested positive underwent HLA DQ typing and endoscopy. RESULTS: Tissue transglutaminase antibodies were positive in six (10%) patients and anti-endomysium in two (3.4%); only two (3.4%), positive for both anti-endomysium positive and anti-transglutaminase, resulted to have coeliac disease based on histological findings. After 6 months of gluten-free diet, liver enzymes normalised. CONCLUSIONS: The prevalence of silent coeliac disease is 3.4% in patients with non-alcoholic fatty liver. The inclusion of anti-endomysium antibodies test in studying patients with non-alcoholic fatty liver and persistent biochemical abnormalities has to be taken into account, since positivity for tissue transglutaminase antibodies, in the absence of confirmatory anti-endomysium antibodies, is not sufficient to perform diagnostic endoscopy.
Assuntos
Autoanticorpos/sangue , Doença Celíaca/diagnóstico , Fígado Gorduroso/complicações , Transglutaminases/imunologia , Adulto , Fatores Etários , Doença Celíaca/complicações , Doença Celíaca/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Antígenos HLA-DQ/sangue , Antígenos HLA-DQ/imunologia , Humanos , Imunoglobulina A/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Insulin resistance is a key feature of nonalcoholic fatty liver disease. Patients with hereditary hemochromatosis, a disease characterized by progressive iron overload due, in most cases, to homozygosity for C282Y mutation in the HFE gene, have often decreased insulin sensitivity and release. AIMS: To determine whether increased iron parameters/heterozygosity for the mutations of the HFE gene confer susceptibility to nonalcoholic fatty liver disease. PATIENTS: One hundred and thirty-four consecutive Italian patients with clinical and ultrasonographic diagnosis of nonalcoholic fatty liver disease (82 with hyperferritinemia), half confirmed by liver biopsy. METHODS: Insulin was determined by radioimmunoassay. HFE gene mutations were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: (1) Prevalence of C282Y HFE mutation was significantly higher in patients with nonalcoholic fatty liver disease compared to controls, the difference being more striking in patients with hyperferritinemia than in those without. (2) The presence of mild iron overload was associated with a lower insulin release. (3) Carriers of C282Y mutation developed nonalcoholic fatty liver disease despite lower body mass index and triglycerides. CONCLUSION: The mild iron overload associated with heterozygosity for C282Y HFE mutation confers susceptibility to nonalcoholic fatty liver disease, causing relative insulin deficiency.
Assuntos
Fígado Gorduroso/genética , Antígenos de Histocompatibilidade Classe I/genética , Resistência à Insulina/genética , Sobrecarga de Ferro/genética , Proteínas de Membrana/genética , Adulto , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Ferritinas/metabolismo , Proteína da Hemocromatose , Heterozigoto , Humanos , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Transferrina/metabolismoRESUMO
A mild to moderate iron excess is found in patients with liver diseases apparently unrelated to genetic hemochromatosis. Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis. A higher frequency of mutations of the HFE gene, the gene responsible for hereditary hemochromatosis, is found in patients with liver diseases and increased liver iron than in normal patients. Patients with excess iron are potentially at a higher risk of developing hepatocellular carcinoma. Iron depletion therapy could interfere with fibrosis development and possibly reduce the risk of liver cancer occurrence.
Assuntos
Hepatopatias/fisiopatologia , Fígado/fisiologia , Proteínas de Membrana , Antígenos HLA/genética , Proteína da Hemocromatose , Hepatite B Crônica/fisiopatologia , Hepatite C Crônica/fisiopatologia , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Hepatopatias/genética , Mutação , Porfiria Cutânea Tardia/fisiopatologiaRESUMO
BACKGROUND/AIM: To test the short-term clinical usefulness of venesection associated with lifestyle counselling as against counselling alone on insulin resistance and liver enzymes in subjects with non-alcoholic fatty liver disease (NAFLD), using a propensity score approach. METHODS: We carried out a 6- to 8-month observational analysis of 198 NAFLD patients in three Italian referral centres (79 venesection and 119 counselling alone). Insulin resistance was measured by the homeostasis model assessment (HOMA) method. Logistic regression was used to identify factors associated with normal HOMA and normal alanine aminotransferase (ALT) at the end of observation. The results were adjusted for the propensity score to be enrolled in the venesection programme, based on clinical and laboratory data, including common HFE polymorphisms and liver biopsy (available in 161 cases). RESULTS: After adjustment for propensity and changes in BMI, venesection was significantly associated with normal HOMA [all cases: odds ratio (OR) 3.00; 95% confidence interval (CI) 1.51-5.97; cases with histology: OR 2.29; 95% CI 1.08-4.87] and ALT within normal limits (all cases: OR 2.56; 95% CI 1.29-5.10; cases with histology: OR 2.81; 95% CI 1.20-5.24). The results were confirmed in an analysis of 57 pairs matched for propensity, where venesection similarly increased the probability of normal HOMA (OR 3.27; 95% CI 1.16-7.84) and normal ALT (OR 5.60; 95% CI 2.09-15.00). Similar data were obtained in the subset of cases with normal basal ferritin (<350 ng/ml). CONCLUSION: Iron depletion by venesection favours the normalization of insulin resistance and raised liver enzymes in non-haemochromatosis patients with NAFLD.