RESUMO
BACKGROUND/AIMS: The nonalcoholic fatty liver disease (NAFLD) activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD. METHODS: One hundred and twenty-nine patients with biopsy-proven NAFLD were included in a long-term histological follow-up study. Clinical course and change in fibrosis stage were compared between nonalcoholic steatohepatitis (NASH), "borderline NASH," and "not NASH" patients. Significant fibrosis progression was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up. RESULTS: Eighty-eight patients accepted reevaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend toward higher baseline NAS was seen in patients (n = 7) who developed end-stage liver disease (3.1 ± 0.9 vs. 2.2 ± 1.0; p = 0.050). Baseline NAS was associated with progressive disease in a univariate binary logistic regression analysis (p = 0.024), but no difference was seen in the multivariate analysis including the NAS, portal inflammation, and perisinusoidal fibrosis. Moreover, 18% of patients without NASH progressed significantly in fibrosis stage. CONCLUSIONS: The ability of the NAS to predict progression of NAFLD is poor. The clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS score groups. To use the NAS as endpoint in treatment trial is not justified.
Assuntos
Progressão da Doença , Fígado Gorduroso/patologia , Cirrose Hepática/patologia , Fígado/patologia , Adulto , Idoso , Biópsia , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico , Feminino , Humanos , Cirrose Hepática/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Hepatopatia Gordurosa não Alcoólica , Valor Preditivo dos Testes , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-α (TNF-α) induces MMPs and may influence anastomosis repair. METHODS: We assessed the efficacies of the nonselective hydroxamate MMP inhibitor GM6001, the selective hydroxamate MMP inhibitor AG3340 and a TNF-α antagonist with respect to anastomotic breaking strength of left-sided colon anastomoses in male Sprague-Dawley rats. RESULTS: Systemic GM6001 treatment effectively blocked MMP activity and maintained the initial breaking strength day 0 of the anastomoses when administered subcutaneously as daily depositions (100 mg/kg) or continuously (10 mg/kg/day). In contrast, the anastomotic biomechanic strength was lowered by 55% (p < 0.001) in vehicle-treated rats on postoperative day 3. GM6001 treatment increased breaking strength by 88% (p < 0.0005) compared with vehicle-treated rats day 3 and reduced (p = 0.003) the occurrence of spontaneous anastomotic dehiscence. Histologically, the anastomotic wound was narrower (p < 0.05) in the longitudinal direction in GM6001-treated animals whereas GM6001 had no significant effect on inflammatory cell infiltration or epithelialization. AG3340 (10 mg/kg) increased (p < 0.012) breaking strength by 47% compared with vehicle on day 3 but did not significantly prevent the reduction of the initial breaking strength on day 0. Although the increased TNF-α levels in the wound were attenuated, the anastomotic breaking strength was not improved (p = 0.62) by the TNF-α (10 mg/kg) inhibitor given systemically. CONCLUSIONS: Pharmacological nonselective MMP inhibition ought to be explored as a prophylactic regimen to reduce anastomotic complications following colorectal resection. The involvement of TNF-α was insignificant in anastomotic wound healing in an experimental model.
Assuntos
Colo/efeitos dos fármacos , Colo/cirurgia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anastomose Cirúrgica , Animais , Colo/patologia , Dipeptídeos/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/enzimologia , Masculino , Metaloproteinases da Matriz/metabolismo , Compostos Orgânicos/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aim of this research was to characterize the mucosa of the gastric cardia in relation to infection with Helicobacter pylori and the occurrence of chronic gastritis in other parts of the stomach in a sample of the general population. In this study, 80 adult volunteers underwent esophagogastroscopy with biopsies from the gastric cardia, corpus, and antrum. Gastritis was classified according to the Sydney system. Chronic gastritis (cardia excepted) was diagnosed in 35 subjects, 30 with H. pylori infection. Epithelial proliferative activity (Ki-67), p53- and p21 expression were examined quantitatively with cell counting after immunohistochemical stainings. Esophagitis was diagnosed macroscopically. Fourty eight subjects had cardia-type and 32 corpus-type mucosa in the anatomical cardia. The prevalence of esophagitis (nine cases) did not differ between these groups. Carditis was more prevalent among subjects with cardia-type mucosa (73 vs. 28%, P < 0.0001). H. pylori was present in 48% of those with cardia-type and 25% of those with corpus-type mucosa (P = 0.06). Of the 44 subjects with carditis, 31 had H. pylori in this location. The group with H. pylori infection had significantly higher mucosal proliferative activity when compared to uninfected subjects. Among the subjects with H. pylori-associated carditis, more p53-positive epithelial cells were detected compared to both the non-infected group (P = 0.0004) and to subjects with non-H. pylori-associated carditis (P = 0.03). In subjects with cardia-type mucosa, and both carditis and gastritis, the degree of chronic inflammation was higher in the cardia compared to the corpus and antrum and the p53 expression was significantly higher in the cardia compared to the corpus, but similar to that in the antrum. The proliferative activity was significantly higher in the antrum compared to the cardia and corpus, respectively. In conclusion, H. pylori infection, carditis, and increased p53 expression are more common in subjects with cardia- than corpus-type mucosa in the gastric cardia. Carditis is mainly related to H. pylori infection. There are some differences regarding inflammation, proliferative activity, and p53 expression between the cardia and other regions of the stomach, yet the significance of these differences remains to be clarified.
Assuntos
Cárdia/patologia , Mucosa Gástrica/patologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Proliferação de Células , Doença Crônica , Feminino , Gastrite/metabolismo , Gastrite/microbiologia , Gastroscopia , Infecções por Helicobacter/metabolismo , Humanos , Inflamação , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD. MATERIAL AND METHODS: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up. RESULTS: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p<0.001) and insulin resistance (p<0.01) were independently associated with significant fibrosis progression. CONCLUSIONS: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Fígado Gorduroso/complicações , Cirrose Hepática/etiologia , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Biópsia , Distribuição de Qui-Quadrado , Progressão da Doença , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Feminino , Humanos , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estatísticas não ParamétricasRESUMO
Adhesion proteins are responsible for the structural integrity of epithelial tissue and in tumors this integrity is often lost, resulting in a disorganization of the tissue. In the present study the complexity of the invasive front of colon carcinomas was correlated with cell adhesion protein expression and with polymorphisms in their genes. A complexity index was constructed from 32 colon carcinomas using computer-assisted morphometry estimating fractal dimension and tumor cell clusters followed by tree analysis. Immunohistochemical staining of beta-catenin, E-cadherin, occludin and claudin 2 was used for assessment of protein expression. Genetic screening of tissue from the tumor invasion front with laser microdissection was performed using SSCP and DNA sequencing. Adhesion protein distribution was significantly disturbed in most carcinomas. A single mutation in the gene of beta-catenin was found but there was no correlation between protein expression and genetic polymorphism. Nor was there any correlation between the complexity of the invasive border and protein distribution or genetic alterations. The results indicate that the complexity of colon carcinoma invasion is not dependent on genetic derangements in the genes of adhesion proteins or the protein distribution. Rather, aberrations in the function of other proteins related to the adhesive proteins could be responsible.
Assuntos
Adenocarcinoma/metabolismo , Caderinas/genética , Caderinas/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Membrana/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Adenocarcinoma/patologia , Claudinas , Neoplasias do Colo/patologia , Genes , Humanos , Imuno-Histoquímica , Invasividade Neoplásica , Ocludina , Polimorfismo GenéticoRESUMO
31P-MRS using DRESS was used to compare absolute liver metabolite concentrations (PME, Pi, PDE, gammaATP, alphaATP, betaATP) in two distinct groups of patients with chronic diffuse liver disorders, one group with steatosis (NAFLD) and none to moderate inflammation (n=13), and one group with severe fibrosis or cirrhosis (n=16). All patients underwent liver biopsy and extensive biochemical evaluation. A control group (n=13) was also included. Absolute concentrations and the anabolic charge, AC=[PME]/([PME]+[PDE]), were calculated. Comparing the control and cirrhosis groups, lower concentrations of PDE (p=0.025) and a higher AC (p<0.001) were found in the cirrhosis group. Also compared to the NAFLD group, the cirrhosis group had lower concentrations of PDE (p=0.01) and a higher AC (p=0.009). No significant differences were found between the control and NAFLD group. When the MRS findings were related to the fibrosis stage obtained at biopsy, there were significant differences in PDE between stage F0-1 and stage F4 and in AC between stage F0-1 and stage F2-3. Using a PDE concentration of 10.5mM as a cut-off value to discriminate between mild, F0-2, and advanced, F3-4, fibrosis the sensitivity and specificity were 81% and 69%, respectively. An AC cut-off value of 0.27 showed a sensitivity of 93% and a specificity of 54%. In conclusion, the results suggest that PDE is a marker of liver fibrosis, and that AC is a potentially clinically useful parameter in discriminating mild fibrosis from advanced.
Assuntos
Cirrose Hepática/patologia , Espectroscopia de Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diagnóstico Diferencial , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Isótopos de Fósforo , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador , Estatísticas não ParamétricasRESUMO
BACKGROUND: Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings. METHODS: Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy; 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data. RESULTS: In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients; at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71%) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed. CONCLUSIONS: Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery.
Assuntos
Doença de Crohn/diagnóstico , Endoscopia Gastrointestinal , Laparotomia , Leucócitos , Compostos Radiofarmacêuticos , Tecnécio Tc 99m Exametazima , Adolescente , Adulto , Idoso , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/cirurgia , Feminino , Humanos , Íleo/diagnóstico por imagem , Íleo/patologia , Intestino Delgado , Período Intraoperatório , Jejuno/diagnóstico por imagem , Jejuno/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Cintilografia , Sensibilidade e EspecificidadeRESUMO
Cyclooxygenase-2 (COX-2) and Bcl-2 have been implicated in upper gastrointestinal tract carcinomas, but the underlying mechanisms are not known. In the present study we assessed the correlation of COX-2 and Bcl-2 to known cell kinetics in the glandular stomach mucosa of 104 Wistar rats given combinations of Helicobacter pylori, MNNG ( N'-methyl- N'-nitro- N-nitrosoguanidine) and bile. COX-2 expression, Bcl-2 and cell proliferation (Ki-67) in antral and corpus mucosa were determined immunohistochemically. Apoptotic cells were detected using terminal uridine deoxynucleotidyl nick end labelling technique. Expression of COX-2 was found in the lower portion of glandular corpus epithelium, and Bcl-2 positivity was mainly seen in the proliferative zone of both antrum and corpus mucosa. COX-2 expression in histologically normal-appearing corpus mucosa was associated with cell proliferation, atrophy and intestinal metaplasia in antrum and with Bcl-2 expression in corpus mucosa. No correlation was found between apoptosis and Bcl-2 expression. MNNG but not H. pylori significantly increased COX-2 in corpus mucosa. H. pylori, however, promoted the COX-2 expression in corpus when bile was added and Bcl-2 expression in antrum. Abnormal expression of both COX-2 and Bcl-2 seem to be involved in H. pylori-induced gastric carcinogenesis by altering the gastric cell kinetics.
Assuntos
Bile/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori , Isoenzimas/biossíntese , Metilnitronitrosoguanidina/toxicidade , Prostaglandina-Endoperóxido Sintases/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Animais , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Ciclo-Oxigenase 2 , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Imuno-Histoquímica , Masculino , Ratos , Ratos WistarRESUMO
This study was designed to investigate human surgical specimens from patients with impingement (n = 16), ruptured supraspinatus tendons (n = 7), frozen shoulder (n = 2) and controls (n = 9) with respect to histological changes and the presence of fibronectin and Matrix metalloprotease-1 (MMP-1). The biopsy of the middle part of the supraspinatus tendons was analyzed microscopically after staining with hematoxyline eosin, Van Giesons hematoxyline and Phospho Tungstic Acid Hematoxyline for visualization of fibrin. Immunofluorescent stainings for fibronectin and MMP-1 were performed. Histology and immunofluorescence were assessed blindly. Necrotic tendinous tissue and fibrin were found only in some specimens from ruptures. The staining for fibronectin was significantly increased among patients with a rupture. MMP-1 was, however, only infrequently found in specimens from patients with impingement and ruptures. Fibrosis and thinning of fascicles seemed to be a more non-specific finding, appearing in control, impingement and rupture specimens. In conclusion, necrotic tendinous tissue, fibrin and fibronectin appear to be signs of tendon degeneration, whereas fibrosis and thinning of fascicles were found also in controls.
Assuntos
Fibronectinas/análise , Metaloproteinase 1 da Matriz/análise , Manguito Rotador/química , Manguito Rotador/patologia , Síndrome de Colisão do Ombro/patologia , Adulto , Biópsia , Fibrose , Imunofluorescência , Humanos , Necrose , Ruptura Espontânea/patologiaRESUMO
Recently a new reference interval for serum ALT, based on samples from up to 3000 healthy adult reference persons, was proposed. In the present study we performed a retrospective analysis of biochemical and histological data from 178 asymptomatic patients currently considered to have increased ALT. Forty-five patients (25%) had serum ALT levels within the new proposed reference interval. Of those, only one had normal liver histology. Of the remaining 44 patients with abnormal liver histology, 34 exhibited fatty infiltration. It is concluded that if the new proposed reference interval for serum ALT is used as "healthy" ranges, the sensitivity of this test in identifying subclinical liver disease will be decreased.
Assuntos
Alanina Transaminase/sangue , Fígado Gorduroso/enzimologia , Adulto , Idoso , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/enzimologia , Fígado/patologia , Hepatopatias/sangue , Hepatopatias/diagnóstico , Hepatopatias/enzimologia , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos RetrospectivosRESUMO
Tumor volume increases during growth and due to tumor progression various mutations appear that may cause phenotypic changes. The invasive pattern may thus be affected resulting in a more disorganized growth. This phenomenon might be due to mutations in the genome of the adhesion proteins, which are responsible for the structural integrity of epithelial tissue. Tumor volume was assessed in whole mount sections of 33 colon carcinomas using Cavalieri's principle. Images from the entire invasive border were captured and used for calculating the irregularity of the border (Complexity Index). The expression of the adhesion proteins E-cadherin, beta-catenin, Claudin 2 and Occludin was assessed after immunohistochemical staining of two randomly selected areas of the invasive front of the tumor. Statistical significance for differences in volume was obtained for tumor Complexity Index, tumor stage (pT) and lymph node status (pN). Expression of adhesion proteins was significantly perturbed in the tumors compared with normal mucosa but only infrequently correlated to tumor differentiation or invasive pattern. The results show that when tumor volume increases the invasive pattern becomes more irregular which is compatible with tumor progression. A direct contribution of adhesion protein derangement to this process appears to be insignificant.
Assuntos
Carcinoma/patologia , Moléculas de Adesão Celular/biossíntese , Neoplasias do Colo/patologia , Carga Tumoral , Caderinas/biossíntese , Carcinoma/metabolismo , Claudinas , Neoplasias do Colo/metabolismo , Humanos , Imuno-Histoquímica , Proteínas de Membrana/biossíntese , Invasividade Neoplásica , Estadiamento de Neoplasias , Ocludina , beta Catenina/biossínteseRESUMO
Helicobacter pylori infection has been linked to hypergastrinemia and either decreased or normal G-cell content in the antral mucosa. To clarify this controversial issue, we quantitatively determined antral G-cell content on the same biopsy specimens with three different methods and examined whether these methods are intercorrelated and the relation of these methods to plasma gastrin concentrations, demography, the occurrence of H. pylori infection and chronic gastritis. Gastric antral mucosal biopsy sections from 273 adults (188 with and 85 without H pylori infection) from a general population sample were examined immunohistochemically for G-cells using cell counting, stereology (point counting) and computerized image analysis. Gastritis was scored according to the updated Sydney system. Basal plasma gastrin concentrations were measured by radioimmunoassay. The three methods for G-cell quantification were poorly correlated and the results showed no correlation with basal plasma gastrin concentrations. The antral G-cell density and scores for H. pylori colonization were positively related to age. Neither the scores for chronic inflammation, nor the scores for inflammatory activity, atrophy or intestinal metaplasia were consistently related to the antral G-cell content. In conclusion, the results of three techniques for G-cell quantification in the gastric antral mucosa were poorly intercorrelated and none of the methods correlated with plasma gastrin concentrations. Age and scores for H pylori colonization seem to be determinants of the G-cell density. That common morphometric techniques correlate poorly is of utmost importance to bear in mind when quantitative morphological studies are planned, compared or interpreted.
RESUMO
Factors determining severity of acute pancreatitis (AP) are poorly understood. Oxidative stress causes acinar cell injury and contributes to the severity, whereas prophylactic probiotics ameliorate experimental pancreatitis. Our objective was to study how probiotics affect oxidative stress, inflammation, and acinar cell injury during the early phase of AP. Fifty-three male Sprague-Dawley rats were randomly allocated into groups: 1) control, 2) sham procedure, 3) AP with no treatment, 4) AP with probiotics, and 5) AP with placebo. AP was induced under general anesthesia by intraductal glycodeoxycholate infusion (15 mM) and intravenous cerulein (5 microg.kg(-1).h(-1), for 6 h). Daily probiotics or placebo were administered intragastrically, starting 5 days prior to AP. After cerulein infusion, pancreas samples were collected for analysis including lipid peroxidation, glutathione, glutamate-cysteine-ligase activity, histological grading of pancreatic injury, and NF-kappaB activation. The severity of pancreatic injury correlated to oxidative damage (r = 0.9) and was ameliorated by probiotics (1.5 vs. placebo 5.5; P = 0.014). AP-induced NF-kappaB activation was reduced by probiotics (0.20 vs. placebo 0.53 OD(450nm)/mg nuclear protein; P < 0.001). Probiotics attenuated AP-induced lipid peroxidation (0.25 vs. placebo 0.51 pmol malondialdehyde/mg protein; P < 0.001). Not only was AP-induced glutathione depletion prevented (8.81 vs. placebo 4.1 micromol/mg protein, P < 0.001), probiotic pretreatment even increased glutathione compared with sham rats (8.81 vs. sham 6.18 miccromol/mg protein, P < 0.001). Biosynthesis of glutathione (glutamate-cysteine-ligase activity) was enhanced in probiotic-pretreated animals. Probiotics enhanced the biosynthesis of glutathione, which may have reduced activation of inflammation and acinar cell injury and ameliorated experimental AP, via a reduction in oxidative stress.
Assuntos
Glutationa/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Probióticos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ceruletídeo , Ácido Glicodesoxicólico , Masculino , Pancreatite/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos EspecíficosRESUMO
BACKGROUND/AIMS: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins. METHODS: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up. RESULTS: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. CONCLUSIONS: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.
Assuntos
Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Fígado/enzimologia , Fígado/patologia , Adulto , Enzimas/sangue , Fígado Gorduroso/tratamento farmacológico , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Adenocarcinoma of the prostate is the most common cancer among men in Western countries. Although the prognostic heterogeneity of prostate cancer is enormous, clinically insignificant aggressive prostate cancers cannot be reliably distinguished. Therefore, identifying prognostic factors is increasingly important, notably among men diagnosed with localized prostate cancer, because many of them may not require aggressive treatment. MATERIALS AND METHODS: We analyzed a population based cohort of 253 men with early stage (T1a-b, Nx, M0) initially untreated prostate cancer diagnosed between 1977 and 1991, before PSA screening was available. Tissue samples were available for 240 patients diagnosed with transurethral resection. During complete followup through September 2003, standardized criteria were used to classify histopathological characteristics, progression and causes of death. RESULTS: Higher Gleason grade, higher nuclear grade and larger tumor volume were independent predictors of death in prostate cancer with monotonous and statistically significant trends (p <0.05). In contrast, the level of Ki-67 - strongly correlated to Gleason score - was not an independent predictor of prostate cancer death. Given a Gleason score of 7 or greater, the probability of dying of prostate cancer was 29%. The corresponding predictive value for Gleason score 8 or greater was 48%. CONCLUSIONS: Although a high Gleason score is a determinant of prostate cancer death, its PPV is relatively low. Thus, further efforts in finding other or complementary indicators of prostate cancer outcome are needed.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Idoso , Seguimentos , Humanos , Masculino , Prognóstico , Suécia , Fatores de TempoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.
Assuntos
Doenças Cardiovasculares/mortalidade , Fígado Gorduroso/mortalidade , Hepatopatias/mortalidade , Fosfatase Alcalina/sangue , Estudos de Coortes , Progressão da Doença , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Feminino , Seguimentos , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Transaminases/sangueRESUMO
The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.
Assuntos
Fígado Gorduroso/patologia , Fígado/patologia , Biópsia/métodos , Humanos , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Different theories have been presented to explain how atrophic gastritis may lead to gastric cancer development. One contributing factor could be impaired function of the gastric mucosal barrier. The aim of this study was to investigate if there are changes in gastric mucosal permeability to sucrose in atrophic gastritis. METHODS: The study comprised 22 patients with atrophic gastritis and 21 normal controls. Gastritis was classified according to the Sydney system from endoscopic biopsies of the gastric corpus and antrum. All subjects were exposed to oral sucrose load (100 g), and the fraction of sucrose excreted in urine was measured by gas chromatography-mass spectrometry. RESULTS: The fraction of sucrose excreted in urine after oral load was significantly increased in atrophic gastritis compared with controls (median 0.08 vs. 0.04%; p = 0.003). Sucrose excretion was positively related to the degree of chronic inflammation (median fraction excreted: mild inflammation 0.06%, moderate inflammation 0.08%, severe inflammation 0.18%; p = 0.04) rather than to the degree of atrophy in the gastric mucosa. Occurrence of intestinal metaplasia was also associated with significantly higher sucrose excretion. However, in multivariate analysis, including intestinal metaplasia, only the degree of inflammation was positively related to sucrose excretion. CONCLUSION: Atrophic gastritis is associated with increased sucrose permeability, suggesting paracellular leakage of the gastric mucosa. This leakage seems to be related to the degree of inflammation rather than the degree of atrophy. The findings may have implications for the diseases and complications associated with atrophic gastritis.
Assuntos
Permeabilidade da Membrana Celular/fisiologia , Mucosa Gástrica/metabolismo , Gastrite Atrófica/metabolismo , Sacarose/farmacocinética , Edulcorantes/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Mucosa Gástrica/patologia , Gastrite Atrófica/patologia , Humanos , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , PrognósticoRESUMO
Helicobacter pylori infection is the main cause of chronic gastritis. The infection has been linked to altered proliferative activity and changes in various cell cycle regulating proteins. To determine, in a general population sample, the proliferative activity and expression of p53 and p21 in males and females of different age groups with and without H. pylori-associated chronic gastritis, gastric biopsies from 273 subjects (188 with and 85 without H. pylori infection) randomly selected from a general population were examined immunohistochemically for Ki-67, p53, and p21. One thousand epithelial cells, including the surface, neck, and glandular areas, were counted in both the corpus and the antrum. Results are expressed as the percentage of positive cells. Subjects with H. pylori infection showed significantly increased proliferative activity and expression of p53 compared to uninfected individuals. Regarding the expression of p21, no difference was detected. Multiple linear regression analysis showed significant associations between chronic inflammation or inflammatory activity, on the one hand, and the degree of proliferation in both the corpus and the antrum, on the other hand. In the antrum, the degree of H. pylori colonization was related to the expression of p53. H. pylori seems to cause increased proliferation and increased expression of p53 (but not p21) in the gastric mucosa, neither of which is age or sex dependent. The proliferative activity is related mainly to events associated with inflammation, while the expression of p53 in the antrum is associated with the degree of H. pylori infection. The action of p53 appears to be independent of p21 activity.
Assuntos
Mucosa Gástrica/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Divisão Celular , Epitélio/metabolismo , Feminino , Gastrite/metabolismo , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
In recent years, Abs have been considered a correlate rather than an effector of resistance against Helicobacter pylori infection. However, it is still poorly understood to what extent Ab production correlates with gastric immunopathology. Here we report that Abs not only are dispensable for protection, but they are detrimental to elimination of the bacteria and appear to impair gastric inflammatory responses. We found that the initial colonization with H. pylori bacteria was normal in the B cell-deficient (microMT) mice, whereas at later times (>8 wk) most of the bacteria were cleared, concomitant with the development of severe gastritis. In contrast, wild-type (WT) mice exhibited extensive bacterial colonization and only mild gastric inflammation, even at 16 wk after inoculation. Oral immunizations with H. pylori lysate and cholera toxin adjuvant stimulated comparable levels of protection in microMT and WT mice. The level of protection in both strains correlated well with the severity of the postimmunization gastritis. Thus, T cells were responsible for the gastritis, whereas Abs, including potentially host cell cross-reactive Abs, were not involved in causing the gastritis. The T cells in micro MT and WT mice produced high and comparable levels of IFN-gamma to recall Ag at 2 and after 8 wk, whereas IL-4 was detected after 8 wk only, indicating that Th1 activity dominated the early phase of protection, whereas later a mixed Th1 and Th2 activity was seen.