RESUMEN
BACKGROUND: Angiogenesis is a proliferative process resulting in the development of new blood vessels from existing endothelial cells and is considered crucial for tumor growth and metastasis. Tumor angiogenesis can be quantified by microvascular density (MVD), which is evaluated in highly vascularized tumor areas (hot spots) by immunohistochemical assays using CD34 and CD31 pan-endothelial antibodies. More recently, CD105 has been successfully used for some tumor types because it could discriminate neovascularization. The expression of CD34 and CD105 in hepatocellular carcinomas (HCC) and hepatic precancerous lesions has been reported-although the results for CD105 are controversial-but to the best our knowledge, CD105 has not been previously investigated in dysplastic nodules (DN). We investigated and compared MVD-CD34 and MVD-CD105 immunoexpression in tissues containing different stages of hepatocarcinogenesis, including DN. METHODS: A total of 31 regenerative nodules (RN), 26 DN and 25 small HCC from explants were used for immunohistochemical tests with CD34 and CD105 antibodies. Antibody expression was quantified by computerized image analysis measurement of MVD, areas containing highly positive endothelial cells within the nodules. RESULTS: The median MVD for CD34 was higher in HCC than in DN and RN (p < 0.01), and was higher in DN compared with RN (p = 0.033). In contrast, MVD with CD105 was higher in RN, and the difference was significant in RN and DN compared with HCC (p = 0.019 and p = 0.012, respectively). When MVD with CD34 and CD105 were compared within a single group, there was a significant predominance of CD105 in RN and DN (p < 0.01). In addition, MVD-C34 in HCC predominated compared with MVD-CD105, but the difference was not statistically significant (p = 0.128). CONCLUSIONS: This study identified a close relationship between CD105 and liver cirrhosis, and that CD34 antibody is a good endothelial marker for hepatic carcinogenesis. There was no difference between the use of CD105 and CD34 antibodies in preneoplastic lesions.
Asunto(s)
Antígenos CD34/análisis , Antígenos CD/análisis , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/irrigación sanguínea , Hiperplasia Nodular Focal/inmunología , Inmunohistoquímica , Neoplasias Hepáticas/irrigación sanguínea , Regeneración Hepática , Microvasos/inmunología , Neovascularización Patológica , Receptores de Superficie Celular/análisis , Automatización de Laboratorios , Carcinoma Hepatocelular/patología , Endoglina , Hiperplasia Nodular Focal/patología , Humanos , Cirrosis Hepática/inmunología , Neoplasias Hepáticas/patología , Microvasos/patología , Valor Predictivo de las PruebasRESUMEN
PURPOSE: Patients with Common Variable Immunodeficiency (CVID) are subject to the development of a liver disease syndrome known as nodular regenerative hyperplasia (NRH). The purpose of this study was to define the characteristics and course of this complication of CVID. METHODS: CVID patients were evaluated by retrospective and prospective clinical course review. Liver biopsy specimens were evaluated for evidence of NRH and studied via RT-PCR for cytokine analysis. RESULTS: NRH in our CVID patient population occurred in approximately 5 % of the 261 patients in our total CVID study group, initially presenting in most cases with an elevated alkaline phosphatase level. While in some patients the disease remained static, in a larger proportion a more severe disease developed characterized by portal hypertension, the latter leading to hypersplenism with neutropenia and thrombocytopenia and, in some cases, to ascites. In addition, a substantial proportion of patients either developed or presented initially with an autoimmune hepatitis-like (AIH-like) liver disease that resulted in severe liver dysfunction and, in most cases to death due to infections. The liver histologic findings in these AIH-like patients were characterized by underlying NRH pattern with superimposed interface hepatitis, lymphocytic infiltration and fibrosis. Immunologic studies of biopsies of NRH patients demonstrated the presence of infiltrating T cells producing IFN-γ, suggesting that the NRH is due to an autoimmune process. CONCLUSION: Overall, these studies provide evidence that NRH may not be benign but, can be a severe and potentially fatal disease complication of CVID that merits close monitoring and intervention.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Citocinas/metabolismo , Hiperplasia Nodular Focal/inmunología , Hígado/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Fosfatasa Alcalina/metabolismo , Autoinmunidad , Niño , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/epidemiología , Citocinas/genética , Femenino , Hiperplasia Nodular Focal/epidemiología , Hiperplasia Nodular Focal/etiología , Estudios de Seguimiento , Humanos , Interferón gamma/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
The association of nodular regenerative hyperplasia with celiac disease is not as well established as it is with hepatopulmonary syndrome and portopulmonary hypertension. IgA anticardiolipin antibodies were reported recently in celiac patients with nodular regenerative hyperplasia. The subject of this study was the description of pulmonary abnormalities and IgA anticardiolipin antibodies in celiac patients with noncirrhotic portal hypertension. Five patients with portal hypertension were investigated to diagnose its etiology. Celiac disease was diagnosed by means of autoantibody reactivity and duodenal biopsies. Liver histology revealed nodular regenerative hyperplasia in four patients and suggested its presence in 1 case. Two cyanotic patients had severe hypoxemia with a confirmed diagnosis of hepatopulmonary syndrome. Another case exhibited features of hepatopulmonary syndrome with increased levels of arterial pulmonary pressure. The remaining 2 cases had slight abnormalities of arterial oxygenation. Three patients had reactivity to IgA anticardiolipin antibodies. The concomitance of celiac disease and nodular regenerative hyperplasia, two infrequent conditions, raises suspicion of there being a nonfortuitous coincidence. Pulmonary abnormalities, and especially hepatopulmonary syndrome, are described for the first time in association with celiac disease and nodular regenerative hyperplasia.
Asunto(s)
Anticuerpos Anticardiolipina/análisis , Enfermedad Celíaca/inmunología , Hiperplasia Nodular Focal/inmunología , Síndrome Hepatopulmonar/inmunología , Adolescente , Adulto , Enfermedad Celíaca/complicaciones , Femenino , Hiperplasia Nodular Focal/complicaciones , Síndrome Hepatopulmonar/complicaciones , Humanos , Hígado/patología , Masculino , Persona de Mediana EdadRESUMEN
Diffuse nodular regenerative hyperplasia (NRH) of the liver is an acquired architectural disturbance that can lead to portal hypertension. Although frequently associated with autoimmune or hematologic malignancies, its exact pathogenesis remains largely unknown. We observed CD8+ cytotoxic T cells in the liver sinusoids of 14 of 44 NRH patients and explored possible relationships between these lymphocytes and vascular damage. The immunophenotype of intrahepatic lymphocytes was determined using immunohistochemical analysis and endothelial injury using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method for apoptosis combined with endothelial cell labeling. Controls for the quantitative analysis of liver-infiltrating lymphocytes consisted of patients with chronic hepatitis C or normal liver (n = 13 and n = 6, respectively). Liver specimens from the 14 patients dislayed intrasinusoidal infiltrate composed of CD3+ and CD8+ lymphocytes, located near atrophic liver cell plates. Significantly more granzyme B+ and CD57+ lymphocytes were observed in NRH than chronic hepatitis C samples with quantitatively similar CD8+ infiltrates. Double-labeling revealed apoptotic endothelial sinusoidal cells in CD8+ T-cell-infiltrated areas in all NRH samples but never in chronic hepatitis C or normal livers. T-cell receptor rearrangement or immunoscope analysis suggested liver-specific polyclonal or oligoclonal T-cell expansions. Clinical and biological characteristics of the 14 patients were similar to those observed in the 30 patients with NRH devoid of lymphocytic infiltration. We report here that CD8+ cytotoxic T cells infiltrated the liver sinusoids of a high percentage (32%) of NRH patients and suggest that some NRH cases might result from chronic, cytotoxic CD8+ T-lymphocyte targeting of sinusoidal endothelial cells.
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Linfocitos T CD8-positivos/inmunología , Hiperplasia Nodular Focal/inmunología , Adulto , Anciano , Apolipoproteínas A , Células Clonales , Femenino , Hiperplasia Nodular Focal/patología , Reordenamiento Génico de Linfocito T , Hepatitis Crónica , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Hígado/inmunología , Masculino , Persona de Mediana EdadRESUMEN
DIAGNOSIS AND PROGNOSIS: Antiphospholipids comprise a very heterogeneous group of auto-antibodies including anticardiolipids demonstrated by immunological methods and lupus anticoagulants detected by coagulation tests. Antiphospholipids are encountered in various conditions other than dysimmune disease and are frequently involved in thrombotic manifestations. We discuss here the implications of these antibodies in digestive tract diseases and present an analysis of their diagnostic and prognostic value for optimal therapeutic and monitoring approaches. CLINICAL MANIFESTATIONS: The risk of thrombosis is high in patients with cryptogenetic inflammatory bowel disease. The prevalence of antiphospholipid antibodies (AcAPL) is abnormally high in these patients, but their contribution to the development of thrombosis remains controversial. Patients with liver disease generally exhibit coagulation disorders, with paradoxical thrombotic manifestations. AcAPL are strongly implicated in the development of thrombosis, particularly in patients with alcoholic liver disease, hepatitis C, regenerative nodular hyperplasia, and cirrhosis, independently of the presence of an associated hepatocellular carcinoma. Antiphospholipid syndrome is considered to be the second leading cause of non-tumor-related Budd-Chiari syndrome, after myeproliferative syndromes. Likewise for portal or mesenteric vein thrombosis where antiphospholipid antibodies would be involved in the causal mechanism. UNDERLYING MECHANISMS: Due to the diversity of these antibodies, it is unlikely that a unique mechanism could explain all the different thrombotic manifestations associated with their presence.
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Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido , Enfermedades del Sistema Digestivo/inmunología , Adulto , Anticuerpos Anticardiolipina/análisis , Anticuerpos Anticardiolipina/inmunología , Anticuerpos Antifosfolípidos/análisis , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/diagnóstico , Síndrome Antifosfolípido/inmunología , Síndrome de Budd-Chiari/inmunología , Enfermedad Celíaca/inmunología , Colitis/inmunología , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Ensayo de Inmunoadsorción Enzimática , Hiperplasia Nodular Focal/inmunología , Hepatitis C/inmunología , Hepatitis Alcohólica/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Hígado/enzimología , Cirrosis Hepática/inmunología , Cirrosis Hepática Alcohólica/inmunología , Hepatopatías/inmunología , Trasplante de Hígado , Prevalencia , Factores de Riesgo , Trombosis/etiología , Trombosis/inmunologíaRESUMEN
Improved imaging techniques have led to an increased detection of suspicious "nodules" in the cirrhotic and noncirrhotic liver. Although the histologic diagnosis of clearly benign or clearly malignant lesions is usually straightforward, problems arise in the differential diagnosis of benign "nodules" and dysplastic lesions or well-differentiated hepatocellular carcinomas. This is especially so in limited diagnostic material, such as cytologic preparations from fine-needle aspirates and needle-core tissue biopsies. Recently, additional helpful markers have been described that may help to establish a conclusive diagnosis even on such material. Two of these, the reticulin stain and immunohistochemical staining for CD34, have been found to be useful also in cytologic cellblock material. Telomerase, a complex enzyme that is active in most malignant tumors, has also been found to show strong activity in most hepatocellular carcinomas. Mention is made of an immunohistochemical marker (MOC-31), reported to be useful in the differentiation between metastatic adenocarcinoma and hepatocellular carcinoma.