RESUMEN
Nonalcoholic fatty liver disease (NAFLD), defined as abnormal accumulation (> 5%) of hepatic triglyceride without excess alcohol intake, is the most common form of chronic liver disease in adults and children in the United States. NAFLD encompasses a spectrum of histologic findings including uncomplicated steatosis, steatosis with inflammation and steatohepatitis [nonalcoholic steatohepatitis (NASH)]; the latter can advance to cirrhosis and hepatocellular carcinoma. NASH is currently accepted as the hepatic manifestation of the set of cardiovascular risk factors collectively known as metabolic syndrome. In 1999 a system for histologic grading and staging for NASH was proposed; this was revised by the NASH Clinical Research Network in 2005 for the entire spectrum of lesions in NAFLD, including the lesions and patterns of pediatric NAFLD, and for application in clinical research trials. Diagnosis remains distinct from grade and stage. A recent European proposal separates steatosis from activity to derive a numeric diagnosis of NASH. Even though there have been promising advancements in non-invasive testing, these tests are not yet detailed enough to replace the full range of findings provided by liver biopsy evaluation. Limitations of biopsy are acknowledged, but liver biopsy remains the "gold standard" for diagnosis and determination of amounts of necroinflammatory activity, and location of fibrosis, as well as remodeling of the parenchyma in NASH. This review focuses on the specific histologic lesions of NAFLD and NASH, grading and staging, differential diagnoses to be considered, and the continuing role of the liver biopsy in this important liver disease.
Asunto(s)
Biopsia , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Adulto , Factores de Edad , Animales , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Niño , Diagnóstico Diferencial , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Oxaliplatin, a component of chemotherapy for colorectal carcinoma liver metastases, can result in hepatic sinusoidal injury; rarely, the injury is fatal. The manifestations of injury are variable. There are no known predictors of susceptibility and outcome. A semi-quantitative system for assessing histological features in non-tumor liver was designed to compare with clinical short-term and long-term outcomes. METHODS: A review of 47 patients with metastatic colorectal carcinoma who received liver resection utilizing a system for an aggregate liver injury score (0-4) included hepatocellular and sinusoidal features. Immunohistochemistry (IHC) for aberrant capillarization was included. The proliferation of hepatocytes and sinusoidal lining cells was evaluated with Ki-67 stain. RESULTS: In total, 32 (68.1%) cases showed light microscopic lesions of oxaliplatin-induced liver injury, in which 26 were moderate to severe. Elevated preoperative aspartate aminotransferase (AST) and alkaline phosphatase levels were noted with higher injury scores (P = 0.01). Patients with higher injury scores had no significant increase in short-term postoperative complications, with one notable exception, who died of liver failure 10 months postoperatively. Increased CD34 expression was associated with higher injury scores (P = 0.00004), and abnormal AST levels (P = 0.04). Preoperative use of bevacizumab was not associated with lower injury scores. Steatosis was correlated with body mass index (P = 0.052) but not with exposure to oxaliplatin, bevacizumab or irinotecan. CONCLUSIONS: The proposed liver injury scoring system encompasses the spectrum of sinusoidal and hepatocellular lesions in oxaliplatin-induced liver injury and is correlated with serum liver enzyme levels in this group. Most patients recovered without complications during the 93-month follow-up, indicating that these lesions are reversible.
Asunto(s)
Antineoplásicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Compuestos Organoplatinos/efectos adversos , Antineoplásicos/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Quimioterapia Adyuvante/efectos adversos , Neoplasias Colorrectales/patología , Femenino , Hepatectomía , Hepatocitos/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Terapia Neoadyuvante/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accordance with NLRC4 acting through transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-interleukin (IL)-10R monoclonal antibody. However, epithelial injury induced by dextran sulfate sodium in mice lacking NLRC4 resulted in a more severe disease, indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation results in production of IL-1ß and IL-18, two cytokines that protect mice from mucosal and systemic challenges.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Unión al Calcio/metabolismo , Colitis/inmunología , Flagelina/metabolismo , Mucosa Intestinal/inmunología , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/inmunología , Células Cultivadas , Colitis/inducido químicamente , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextran/administración & dosificación , Modelos Animales de Enfermedad , Flagelina/genética , Flagelina/inmunología , Humanos , Inmunidad Innata/genética , Ratones , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/inmunologíaRESUMEN
INTRODUCTION: Liver ischemia-reperfusion (I/R) injury is a well-known cause of morbidity and mortality following liver surgery and transplantation. Hepatic steatosis increases the extent of cellular injury incurred during I/R injury. We sought to identify measures that reduced the untoward sequelae of liver I/R injury. METHODS: Male Zucker rats were subjected to 75 minutes of 70% hepatic ischemia, and 3 hours of reperfusion. The ischemic periods were based on the following protocols: continuous clamping (CC) for 75 minutes; intermittent clamping (IC) with five cycles of 15 minutes clamp on and 5 minutes clamp off; or ischemic preconditioning (IP) with 10 minutes clamp on, 15 minutes off, and 60 minutes on (n=7 in each group). Warm I/R injury was evaluated using serum levels of aspartate aminotransferase (AST), serum interleukin (IL)-6, as well as hematoxylin and eosin staining. RESULTS: Hepatocellular injury was significantly reduced with IP or IC compared with CC (AST: 3285+/-122.3 and 2875+/-285.4 compared with 5436.3+/--984.7 units/L, respectively; P<.01). Serum IL-6 level was also significantly reduced with IP and IC compared with CC (70+/-8.8 and 76+/-6.2 compared with 147+/-8.5 ng/l, respectively (p<.01). Histological analysis also revealed that IC and IP provided significant protection compared with the CC group. CONCLUSION: IC and IP increased the tolerance of a fatty liver to hepatic I/R injury.