酒精性肝病患者血清瘦素水平与肝纤维化的关系

瘦素(leptin)是由肥胖基因编码的产物。实验研究显示活化的肝星状细胞(HSC)瘦素合成明显增加,提示瘦素可能与肝纤维化有关。现拟探讨酒精性肝病患者血清瘦素水平与肝组织纤维化的关系。 1.资料与方法:(1)研究对象:酒精性肝病(ALD)患者60例,均为男性,诊断依据2001年中华医学会肝病学分会脂肪肝酒精肝学组制定的“酒精性肝病诊断标准”。酒精性脂肪肝14例,     

瘦素及其受体在大鼠酒精性肝病形成过程中的动态变化及意义

目的:观察酒精性肝病形成中大鼠血清瘦素水平、肝组织瘦素及其受体表达的动态变化,探讨瘦素及其受体在酒精性肝病形成中的发病机制.方法:SD雄性大鼠随机分为正常组和模型组,以白酒-玉米油-吡唑混合液灌胃建立酒精性肝病动物模型,分别在4、8、14周末光镜观察大鼠肝脏组织学变化情况,免疫组化法检测肝组织瘦素及其受体的表达,ELISA法检测大鼠血清瘦素水平.结果:模型组大鼠肝组织在4周时出现轻度脂肪变及腺泡内个别点状坏死灶,8周时脂肪变程度加重、腺泡内点状坏死灶增多、门管区炎细胞浸润,14周脂肪变和炎症程度进一步加重;模型组大鼠4周时,肝组织瘦素及其受体表达、血清瘦素水平与同期正常组比差异无显著性意义(P＞0.05),随着肝脏损伤程度的加重,三者均明显增加(P＜0.05,P＜0.01);肝组织中瘦素及其受体表达水平与肝脏脂肪变及炎症程度均呈明显正相关.结论:在白酒-玉米油-吡唑混合液灌服复制的大鼠酒精性肝病形成过程中,瘦素及其受体表达增加,且随肝脏损伤程度的加重而逐渐增加,提示其参与了酒精性肝病的发生发展.     

Dynamic changes of key metabolites during liver fibrosis in rats

BACKGROUND Fibrosis is the single most important predictor of significant morbidity and mortality in patients with chronic liver disease.Established non-invasive tests for monitoring fibrosis are lacking,and new biomarkers of liver fibrosis and function are needed.AIM To depict the process of liver fibrosis and look for novel biomarkers for diagnosis and monitoring fibrosis progression.METHODS CCl4 was used to establish the rat liver fibrosis model.Liver fibrosis process was measured by liver chemical tests,liver histopathology,and Masson’s trichrome staining.The expression levels of two fibrotic markers includingα-smooth muscle actin and transforming growth factorβ1 were assessed using immunohistochemistry and real-time polymerase chain reaction.Dynamic changes in metabolic profiles and biomarker concentrations in rat serum during liver fibrosis progression were investigated using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.The discriminatory capability of potential biomarkers was evaluated by receiver operating characteristic(ROC)curve analysis.RESULTS To investigate the dynamic changes of metabolites during the process of liver fibrosis,sera from control and fibrosis model rats based on pathological results were analyzed at five different time points.We investigated the association of liver fibrosis with 21 metabolites including hydroxyethyl glycine,L-threonine,indoleacrylic acid,β-muricholic acid(β-MCA),cervonoyl ethanolamide(CEA),phosphatidylcholines,and lysophosphatidylcholines.Two metabolites,CEA andβ-MCA,differed significantly in the fibrosis model rats compared to controls(P<0.05)and showed prognostic value for fibrosis.ROC curve analyses performed to calculate the area under the curve(AUC)revealed that CEA andβ-MCA differed significantly in the fibrosis group compared to controls with AUC values exceeding 0.8,and can clearly differentiate early stage from late stage fibrosis or cirrhosis.CONCLUSION This study identified two novel biomarkers of fibrosis,CEA andβ-MCA,which were effective for diagnosing fibrosis in an animal model.     

酒精性肝病的流行病学

酒精滥用和酒精依赖已成为当今世界上日益严重的公共卫生问题,特别是青少年饮酒更值得人们重视。我国酒类产量1984年为711.3万吨,2001年达到3 069.87万吨。对我国4大地区饮酒情况的流行病学调查表明,一般人群的饮酒率为59.5％,其中男性84.6％,女性29.4％,人均年饮酒量3.6 L纯酒精。 酒精对肝脏有明显的毒性作用,重度饮酒精者中80％以上有一定程度的脂肪肝,10％-35％可发展成酒精性肝炎,10％-20％将发展为肝硬化。美国酒精性肝病死亡居第10位,每年约     

Dendritic cells in alcoholic liver injury and fibrosis

Alcohol consumption impairs the development of innate and adaptive immune responses, however the exact mechanism by which alcohol leads to immune defects remains to be established. Dendritic cells (DCs) form a heterogeneous population of hematopoietic cells that are present in all tissues including the liver. DC are initially described playing a key role in the induction of innate and adaptive immune response against specific antigens. In our presentation, we discussed few new aspects of DC development, critical assessment of DC in non-lymphoid organs and the impact of alcohol consumption on DC function. Understanding the mechanism by which DC modulate liver function after alcohol consumption may help uncover novel therapeutic strategies for the treatment of these conditions.     

Liver fibrosis markers in alcoholic liver disease

Alcohol is one of the main factors of liver damage. The evaluation of the degree of liver fibrosis is of great value for therapeutic decision making in patients with alcoholic liver disease (ALD). Staging of liver fibrosis is essential to define prognosis and management of the disease. Liver biopsy is a gold standard as it has high sensitivity and specificity in fibrosis diagnostics. Taking into account the limitations of liver biopsy, there is an exigency to introduce non-invasive serum markers for fibrosis that would be able to replace liver biopsy. Ideal serum markers should be specific for the liver, easy to perform and independent to inflammation and fibrosis in other organs. Serum markers of hepatic fibrosis are divided into direct and indirect. Indirect markers reflect alterations in hepatic function, direct markers reflect extracellular matrix turnover. These markers should correlate with dynamic changes in fibrogenesis and fibrosis resolution. The assessment of the degree of liver fibrosis in alcoholic liver disease has diagnostic and prognostic implications, therefore noninvasive assessment of fibrosis remains important. There are only a few studies evaluating the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. Several noninvasive laboratory tests have been used to assess liver fibrosis in patients with alcoholic liver disease, including the hyaluronic acid, FibroTest, FibrometerA, Hepascore, Forns and APRI indexes, FIB4, an algorithm combining Prothrombin index (PI), α-2 macroglobulin and hyaluronic acid. Among these tests, Fibrotest, FibrometerA and Hepascore demonstrated excellent diagnostic accuracy in identifying advanced fibrosis and cirrhosis, and additionally, Fibrotest was independently associated with survival. Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of alcoholic patients.     

Zinc depletion in alcoholic liver diseases

Liver and serum zinc concentrations were investigated in 24 patients with alcoholic liver diseases, 22 patients with non-alcoholic liver diseases, and in 36 control subjects. The liver samples were obtained by percutaneous liver biopsies, and the ratio of hepatocytes to fibrous connective tissue was estimated. The liver zinc concentration was expressed in relation to the amount of hepatocytes, and the serum zinc concentration was calculated in relation to total, albumin-, and alpha 2-macroglobulin-bound serum zinc. The results show that the liver zinc concentration was decreased in patients with alcoholic liver diseases (P < 0.01), in contrast to in patients with non-alcoholic liver diseases. Albumin-bound serum zinc was decreased in both groups (P < 0.001). The results indicate that alcoholic liver damage is associated with zinc deficiency.     

Changes in liver and spleen volume in alcoholic liver fibrosis of man

Alcoholic liver fibrosis is a relatively common form of alcoholic liver disease in Japan. It is regarded by some investigators as a prodromal stage of alcoholic liver cirrhosis, but little is known about the volumes of the liver and spleen in this disease state. Therefore, liver and spleen volumes were measured by computed tomography in 32 patients with alcoholic liver fibrosis in comparison with 10 healthy volunteers. Patients with alcoholic liver fibrosis were divided into three subgroups (13 of Grade 1, 9 of Grade 2 and 10 of Grade 3) according to the severity of fibrosis. The volume was calculated from the sum of the area measurements of successive transverse sections of the two organs. The liver volume (mean +/- S.D.) in Grade 2 alcoholic liver fibrosis (1,281 +/- 112 cm3) was significantly (p less than 0.01) larger than in healthy volunteers (1,017 +/- 73 cm3) and in Grade 1 (1,090 +/- 157 cm3), and the liver volume in Grade 3 (1,490 +/- 132 cm3) was larger than in Grade 2 (p less than 0.01). The mean volume of hepatocytes estimated by a two-dimensional image analysis system was significantly (p less than 0.05) larger in Grade 3 than in Grade 2, and that in Grade 2 was larger than in Grade 1. The spleen volume in Grade 3 (151 +/- 40 cm3) was significantly (p less than 0.01) larger than in healthy volunteers (86 +/- 26 cm3), Grade 1 (89 +/- 38 cm3) and Grade 2 (68 +/- 19 cm3). The presumed reason for hepatic volume increase would be the ballooning of hepatocytes along with increased fibrotic component.     

Bone changes in alcoholic liver cirrhosis

Bone biopsies of 52 histologically confirmed alcoholic cirrhotic patients and 15 age- and sex-matched controls have been histomorphometrically analyzed determining trabecular bone volume (TBV), mineralized bone volume (MBV), and osteoid volume (OV). We also determined serum PTH, 25-OH-D3, calcitonin, FSH, LH, estradiol, testosterone, T3 and T4, urine cortisol, routine liver function tests, serum and urinary calcium, phosphorus, and magnesium. We found a high prevalence of osteoporosis: TBV was significantly lower in cirrhotic patients (T = 7.23, P less than 0.001), 41 of them being in the range of osteoporosis; none of them had osteomalacia. Levels of all the above-mentioned hormones and electrolytes were almost normal, and no correlation was found between them and liver function tests, as occurred with the bone parameters.     

Bone changes in alcoholic liver disease

Alcoholism has been associated with growth impairment, osteomalacia, delayed fracture healing, and aseptic necrosis (primarily necrosis of the femoral head), but the main alterations observed in the bones of alcoholic patients are osteoporosis and an increased risk of fractures. Decreased bone mass is a hallmark of osteoporosis, and it may be due either to decreased bone synthesis and/or to increased bone breakdown. Ethanol may affect both mechanisms. It is generally accepted that ethanol decreases bone synthesis, and most authors have reported decreased osteocalcin levels (a “marker” of bone synthesis), but some controversy exists regarding the effect of alcohol on bone breakdown, and, indeed, disparate results have been reported for telopeptide and other biochemical markers of bone resorption. In addition to the direct effect of ethanol, systemic alterations such as malnutrition, malabsorption, liver disease, increased levels of proinflammatory cytokines, alcoholic myopathy and neuropathy, low testosterone levels, and an increased risk of trauma, play contributory roles. The treatment of alcoholic bone disease should be aimed towards increasing bone formation and decreasing bone degradation. In this sense, vitamin D and calcium supplementation, together with biphosphonates are essential, but alcohol abstinence and nutritional improvement are equally important. In this review we study the pathogenesis of bone changes in alcoholic liver disease and discuss potential therapies.     

酒精性肝病的影像学诊断

1.酒精性脂肪肝:脂肪肝包括弥漫性脂肪肝(均匀性脂肪肝)及限局性脂肪肝(非均匀性脂肪肝)。超声:弥漫性脂肪肝肝脏普遍增大,包膜光滑,肝实质回声增强,呈弥漫性细点状,为亮肝。肝内回声强度随深度而衰减(声衰减现象),肝内血管回声减弱或显示不清。限局性脂肪肝分二型:(1)叶段型:多数病变分布呈叶段型.肝实质内呈现片状回声增强区,常以肝叶段为界或沿门静脉分支长轴分布,边界清楚,无占位效应。(2)     

Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease

Alcoholic liver disease(ALD) consists of a broad spectrum of disorders, ranging from simple steatosisto alcoholic steatohepatitis and cirrhosis. Fatty liver develops in more than 90% of heavy drinkers, however only 30%-35% of them develop more advanced forms of ALD. Therefore, even if the current "gold standard" for the assessment of the stage of alcohol-related liver injury is histology, liver biopsy is not reasonable in all patients who present with ALD. Currently, although several non-invasive fibrosis markers have been suggested as alternatives to liver biopsy in patients with ALD, none has been sufficiently validated. As described in other liver disease, the diagnostic accuracy of such tests in ALD is acceptable for the diagnosis of significant fibrosis or cirrhosis but not for lesser fibrosis stages. Existing data suggest that the use of noninvasive tests could be tailored to first tier screening of patients at risk, in order to diagnose early patients with progressive liver disease and offer targeted interventions for the prevention of decompensation. We review these tests and critically appraise the existing evidence.     

Colchicine for alcoholic and non‐alcoholic liver fibrosis or cirrhosis

Abstract: Aims/Background: Colchicine is an anti‐inflammatory and anti‐fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non‐alcoholic fibrosis and cirrhosis. The objectives were to assess the efficacy of colchicine evaluated in randomized trials on mortality, liver related mortality, liver related complications, liver fibrosis markers, liver histology, alcohol consumption, quality of life, and health economics in patients with alcoholic and non‐alcoholic fibrosis or cirrhosis. Methods: Interventions encompassed peroral colchicine at any dose versus placebo or no intervention. The trials could be double‐blind, single‐blind or unblinded. The trials could be unpublished or published as an article, an abstract, or a letter, and no language limitations were applied. All analyses were performed according to the intention‐to‐treat method. MEDLINE, The Cochrane Controlled Trials Register, The Cochrane Hepato‐Biliary Group Controlled Trials Register and full text searches were combined. Results: Combining the results of 14 randomized clinical trials including 1138 patients demonstrated no significant effects of colchicine on mortality (odds ratio (OR): 0.91; 95% confidence interval (CI) 0.64, 1.31), liver related mortality (OR: 0.98; CI 0.56, 1.74), complications (OR: 1.06; CI 0.65, 1.73), and the other outcomes. Colchicine was associated with a significantly increased risk of adverse events (OR: 4.41; CI 2.24, 8.70; p< 0.001). Conclusions: Colchicine should not be used for liver fibrosis or liver cirrhosis irrespective of etiology. Future trials on colchicine for liver diseases ought to be large.     

Value of fibrosis markers for staging liver fibrosis in patients with precirrhotic alcoholic liver disease

Background: Our aim was to identify markers predictive of fibrosis in alcoholic liver disease (ALD). Percutaneous liver biopsy is the recommended standard for histologic assessment of liver fibrosis. Seven serum markers (tissue inhibitor of matrix metalloproteinase 1 {TIMP1}, tenascin, collagen VI, amino‐terminal propeptide of type III collagen {PIIINP}, matrix metalloproteinases {MMP2}, laminin, and hyaluronic acid {HA}) representing various aspects of collagen and extracellular matrix deposition and degradation, have been proposed as noninvasive surrogates for liver biopsy. Moreover, a diagnostic algorithm including 3 serum markers (TIMP1, PIIINP, HA) and age has been proposed to accurately detect fibrosis with acceptable levels of sensitivity/specificity in a chronic hepatitis C subgroup. Methods: To determine variability of these markers in liver fibrosis with different etiologies, we conducted an evaluation of their correlative properties in a subgroup of patients (n = 247) with biopsy confirmed liver fibrosis resulting from long‐term heavy alcohol consumption. Patients were participants in a recently completed VA multicenter clinical trial followed over 2 years with liver biopsy at baseline and 24 months, and with markers assessed every 3 months. Results: Among the markers measured in this alcoholic subgroup all except collagen VI displayed significant correlation with degrees of fibrosis. Three markers, TIMP1, PIIINP and HA adjusted for age, emerged as the most promising predictors of the degree of fibrosis in a population of alcoholics. However, there was little change over time as related to change in fibrosis. The lower than expected accuracy of these markers based on receiver operating curves (ROC) also showed their limited use in this etiologic subgroup. Conclusion: In alcoholic patients, various markers have limited value in predicting and diagnosing the stages of fibrosis compared to liver biopsy. Thus, further prospective studies are required to better define the usefulness of each marker or their combination which are possibly affected by alcohol metabolism.