Effect of H pylori infection and its eradication on hyperammo-nemia and hepatic encephalopathy in cirrhotic patients

AIM: To investigate the relationship between H pylori infection, blood ammonia concentration and hepatic encephalopathy (HE), and the effect of H pylori eradication in cirrhotic patients.METHODS: From July 2003 to January 2005, 457 cirrhotic patients in five regions of Zhejiang Province were enrolled. Patients were evaluated for demographics, number connection test, H pylori infection, liver impairment, blood ammonia concentration and HE. Patients with H pylori infection were given 1 wk therapy with omeprazole plus clarithromycin and tinidazole. 14C urea breath test was performed and mental symptoms and blood ammonia level were reassessed after bacterium eradication.RESULTS: Overall H pylori infection rate was 60.6%, and HE occurred in 47.5% of cirrhotic patients. Subclinical HE (SHE) was detected in 55 of 117 cirrhotic patients. Blood ammonia concentration in H pylori negative (n = 180) and positive (n = 277) cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 nmol/L, respectively (P < 0.01), which was significantly reduced to 53.5 ± 37.7 nmol/L after bacterium eradication (n = 126) (P < 0.01). Blood ammonia was 97.5 ± 81.0 nmol/L in H py/ori-positive cirrhotic patients, and this did not significantly change in those with persistent infection after H pylori eradication (n = 11). HE was more frequently observed in patients with H pylori infection than in those without (58.5% vs 30.6%, P < 0.01). HE rate significantly dropped to 34.1% after H pylori eradiation (P < 0.01). H pylori prevalence significantly differed among cirrhotic patients with HE (74.4%), SHE (69.1%), and those without HE (53.2%) (P < 0.05). Blood ammonia level was significantly different among cirrhotic patients with HE (94.5 ± 75.6 nmol/L), SHE (59.9 ± 49.2 nmol/L), and without HE (47.3 ± 33.5 nmol/L) (P < 0.05). Logistic regression analysis showed that blood ammonia concentration, Child-Pugh stage, upper gastrointestinal bleeding, electrolyte disturbance, and urea nitrogen were risk factors for HE.CONCLUSION: H pylori infection is an important factor for inducing high blood ammonia concentration and HE in cirrhotic patients. H pylori eradication may be helpful for treatment and prevention of HE.     

Effect of H pylori infection and its eradication on hyperammo-nemia and hepatic encephalopathy in cirrhotic patients

AIM： To investigate the relationship between H pylori infection, blood ammonia concentration and hepatic encephalopathy （HE）, and the effect of Hpylori eradication in cirrhotic patients. METHODS： From July 2003 to January 2005, 457 cirrhotic patients in five regions of Zhejiang Province were enrolled. Patients were evaluated for demographics, number connection test, Hpylori infection, liver impairment, blood ammonia concentration and HE. Patients with Hpylori infection were given I wk therapy with omeprazole plus clarithromycin and tinidazole. ^14C urea breath test was performed and mental symptoms and blood ammonia level were reassessed after RESULTS： Overall H pylori infection rate was 60.6%, and HE occurred in 47.5% of cirrhotic patients. Subclinical HE （SHE） was detected in 55 of 117 cirrhotic patients. Blood ammonia concentration in H pylori negative （n = 180） and positive （n = 277） cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 μmol/L, respectively （P 〈 0.01）, which was significantly reduced to 53.5 ± 37.7 μmol/L after bacterium eradication （n = 126） （P 〈 0.01）. Blood ammonia was 97.5 ± 81.0 μmol/L in H pylori-positive cirrhotic patients, and this did not significantly change in those with persistent infection after Hpylori eradication （n = 11）. HE was more frequently observed in patients with H pylori infection than in those without （58.5% vs 30.6%, P 〈 0.01）. HE rate significantly dropped to 34.1% after H pylori eradiation （P 〈 0.01）. H pylori prevalence significantly differed among cirrhotic patients with HE （74.4%）, SHE （69.1%）, and those without HE （53.2%） （P 〈 0.05）. Blood ammonia level was significantly different among cirrhotic patients with HE （94.5 ± 75.6 μmol/L）, SHE （59.9 ± 49.2 μmol/L）, and without HE （47.3 ± 33.5 μmol/L） （P 〈 0.05）. Logistic regression analysis showed that blood ammonia concentration, Child-Pugh stage, upper gastrointestinal bleeding, electrolyte disturbance, and urea nit     

胰岛素样生长因子1与原发性高血压

目的:探讨原发性高血压病的发病机制。方法:对28例原发性高血压患者和16名正常人测定了血清胰岛素样生长因子1(IGF1),并与高血压分级进行了相关分析。结果:原发性高血压患者IGF1水平显著低于正常人(分别为26.22μg/L±20.23μg/L和48.02μg/L±33.43μ/L,P<0.05),且IGF1水平与临床分级呈负相关(=-0.437,P<0.05)。 结论:IGF1可能参与了原发性高血压的病理生理过程。     

宫内发育迟缓与胰岛素样生长因子及其结合蛋白关系的研究

为探讨宫内发育迟缓（IUGR）的发生机制,检测了86例新生儿脐血胰岛素样生长因子－1（IGF－1）、胰岛素样生长因子结合蛋白－3（IGFBP－3）水平,并分析上述指标变化与胎儿期生长的关系。将86例新生儿分为两组,IUGR（即小于胎龄儿）组22例,适于胎龄儿（AGA）组64例,采用竞争性放射免疫分析法（RIA）测定两组脐血IGF－1水平,非竞争性免疫放射分析法（IRMA）测定IGFBP－3水平。结果显示,与AGA组相比,IUGR组脐血IGF－1和IGFBP－3水平显著降低（P＜0．001）;IGF－1水平随胎龄及出生体重增加而增加（P＜0．01）;IGFBP－3水平与胎龄及出生体重呈相关（P＜0．01）;IGF－1与IGFBP－3呈正相关（P＜0．01）。认为IUGR与IGF－1及其结合蛋白密切相关,不论何种原因引起的IUGR,其脐血IGF－1、IGFBP－3水平均低,IGF－1水平下降与IGFBP－3下降相伴随;脐血IGF－1、IGFBP－3水平与胎龄及出生体重呈正相关,随着胎龄的增加和出生体重的增长,IGF－1、IGFBP－3水平不断升高。     

罗格列酮对免疫性肝纤维化大鼠肝组织IGF-1表达的影响

目的探讨免疫性肝纤维化大鼠肝组织中胰岛素样生长因子-1(IGF-1)的表达变化,并观察罗格列酮对其的影响。方法应用猪血清腹腔注射诱导大鼠肝纤维化模型,适时给予罗格列酮干预。采用ELISA法检测血清IGF-1水平和免疫组织化学法检测肝组织IGF-1的表达。结果与对照组相比,第4、6、8周模型组大鼠血清及肝组织IGF-1水平均显著升高(P<0.05);与模型组相比,8周罗格列酮组大鼠纤维化程度减轻(P<0.01),血清及肝组织IGF-1表达水平降低(P<0.01)。结论随肝纤维化进展,大鼠血清和肝组织IGF-1的表达均增强,罗格列酮可降低肝组织IGF-1的表达,因而能减轻大鼠肝纤维化。     

肺癌患者胰岛素样生长因子1和胰岛素样生长因子结合蛋白3的表达及其临床意义

目的 分析肺癌患者血清和支气管肺泡灌洗液（BALF）中胰岛素样生长因子1（IGF-1）、胰岛素样生长因子结合蛋白3（IGFBP-3）的表达,探讨其在肺癌诊断和预后中的临床意义.方法 运用免疫放射法检测80例非小细胞肺癌患者和14名健康者（对照组）外周血血清与BALF中IGF-1、IGFBP-3的水平.结果 肺癌组血清和BALF中IGF-1表达显著高于对照组（P＜0.01）,IGFBP-3的表达显著低于对照组（P＜0.05）,同时IGF-1/IGFBP-3升高（P＜0.01）.IGF-1、IGF-1/IGFBP-3在有淋巴结转移、远处转移和TNMⅢ～Ⅳ的肺癌患者血清、BALF中明显高于无转移者和TNMⅠ～Ⅱ期者（P＜0.05）,而IGFBP3下降明显高于无转移者及TNMⅠ～Ⅱ期者（P＜0.05）.肺癌组血清IGF-1、IGFBP-3浓度与BALF中的浓度呈正相关（P ＜0.01）;患者血清BALF中IGF-1与IGFBP-3浓度呈负相关（P＜0.05）.结论 非小细胞肺癌患者血清和支气管肺泡灌洗液中IGF-1、IGFBP-3的表达对肺癌的诊断、判断预后有重要临床意义.     

非霍奇金淋巴瘤患者血清胰岛素样生长因子-1及其结合蛋白-3表达水平的初步观察

目的:探讨非霍奇金淋巴瘤(NHL)患者血清胰岛素样生长因子-1(IGF-1)及其结合蛋白-3(IGFBP-3)表达水平及其临床意义.方法:选择28例诊断初发NHL患者(淋巴瘤组)及28例健康志愿者(对照组),化学发光法测定血清IGF-1及IGFBP-3水平并计算IGF- 1/IGFBP-3值,分析组间的差异.结果:血清IGF-1及IGFBP-3水平淋巴瘤组显著低于正常对照组(均P＜0.01);IGF-1/IGFBP-3淋巴瘤组与正常对照组差异无统计学意义(P＞0.05);不同亚型的淋巴瘤组的血清IGF-1、IGFBP-3水平及IGF-1/IGFBP-3比值的差异均未达到统计学意义(P＞0.05).结论:N HL患者血清IGF-I及IGFBP-3水平明显降低,可能与NHL相关.IGF-1/IGFBP-3比值与NHL无明显相关性,IGF-1及IGFBP-3水平与NHL的分型无明显相关.     

The insulin-like growth factor system and the fetal brain: Effects of poor maternal nutrition

The insulin-like growth factor (IGF) signaling system plays indispensable roles in pre- and post-natal brain growth and development. A large body of studies using both in vivo null mutant and transgenic mice and in vitro neuronal culture techniques indicate that IGF-I acts directly on the brain while IGF-II effects are mediated to a large extent by IGF-II control of placental growth. It appears that all of the mechanisms, except migration, that are involved in normal brain development, e.g., proliferation, apoptosis, maturation and differentiation, are influenced by IGF-I. While IGF system members are produced in the brain, recent reports in post-natal animals indicate that normal brain health and function are dependent upon transfer of circulating IGF-I from the liver and its transfer across the blood brain barrier. Data showing that this phenomenon applies to pre-natal brain growth and development would make an important contribution to fetal physiology. A number of kinase pathways are able to participate in IGF signaling in brain with respect to nutrient restriction; among the most important are the PI3K/AKT, Ras–Raf–MEK–ERK and mTOR-nutrient sensing pathways. Both maternal and fetal IGF-I peripheral plasma concentrations are greatly reduced in nutrient restriction while IGF-II does not appear to be affected. Nutrient restriction also affects IGF binding protein concentrations while effects on the IGF-I receptor appear to vary with the paradigm. Studies on the effects of nutrient restriction on the fetal primate brain in relation to activity of the IGF system are needed to determine the applicability of rodent studies to humans.     

Regulation of insulin-like growth factor binding protein-1 (IGFBP-1) in insulin-dependent diabetes mellitus

The aim of the present study was to characterize the effect of 44 h of hyperglycaemia on diurnal levels of insulin-like growth factor binding protein-1 (IGFBP-1), insulin-like growth factor-1 (IGF-1), growth hormone (GH) and glucagon in 7 well-controlled subjects with insulin-dependent diabetes mellitus (IDDM). Hyperglycaemia (15 mmol/l) was induced by a glucose infusion, while the degree of insulinisation was similar to that of a corresponding period with near normoglycaemia (6.9 mmol/l). Hyperglycaemia for 44 h did not alter the normal diurnal IGFBP-1 levels when the degree of insulinisation was unchanged. The diurnal secretion pattern of IGFBP-1 was preserved in both genders and without any difference between the control and hyperglycaemic periods. However, the IGFBP-1 levels were increased in these IDDM subjects despite a peripheral hyperinsulinemia. An inverse correlation was found between IGFBP-1 and peripheral insulin levels both during periods of rapid changes in IGFBP-1 and insulin concentrations (i.e. morning hours) as well as during the total 24-h sampling period. Total IGF-1 levels were low, but no further decrease was seen after 24 h of hyperglycaemia in the presence of unchanged insulin levels. In conclusion, the present study clearly shows that the increased IGFBP-1 level seen during poor metabolic control in IDDM is not caused by hyperglycaemia. Glucose levels per se do not influence either total IGF-1 or IGFBP-1 concentrations in well-insulinised diabetic patients.     

Role of growth hormone, insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 in development of non-alcoholic fatty liver disease

Background and aims Pituitary dysfunction including growth hormone (GH) deficiency may be associated with non-alcoholic fatty liver disease (NAFLD). Since the relationships among GH, IGF-1, IGFBP-3, and development of NAFLD without hypopituitarism are unclear, we examined the role of these hormones in the development of NAFLD based on clinical, laboratory and liver histology data. Patients and methods A total of 55 consecutive patients (20 males and 35 females) with NAFLD. Results Aspartate amino transferase (AST), AST/ALT, platelet count and IGF-1, levels were significantly associated with differences in fibrosis, since these variables differed between stage 0–1 and stage 2–3 NAFLD. In multivariate analysis, platelet count (P = 0.0223, relative risk (RR), 5.899; 95% confidence interval (CI), 1.288–27.017), and IGF-1 (P = 0.0363, RR, 4.568; 95% CI, 1.101–18.945) showed significant associations with stage 2–3 NAFLD. Additionally, hyaluronic acid levels had a negative relationship with IGF-1 and the IGF-1/IGFBP-3 ratio. There was no relationship of fibrosis with GH level, but decreased GH (P = 0.0414, RR, 0.199; 95% CI, 0.042–0.989) was significantly associated with steatosis of stage 2–3. Low GH/IGF-1 and GH/IGFBP-3 ratios were found in advanced steatosis. Conclusion GH, IGF-1 and IGFBP-3 are associated with hepatic fibrosis and steatosis in NAFLD. Low levels of IGF-1 might be associated with fibrosis while low level of GH with hepatic steatosis.     

MELD score, insulin-like growth factor 1 and cytokines on bone density in end-stage liver disease

AIM:To determine the contributions of insulin-like growth factor 1 (IGF-1),cytokines and liver disease severity to bone mineral density in patients pre-transplantation.METHODS:Serum IGF-1,tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6) were measured and the Model for End-Stage Liver Disease (MELD) score calculated in 121 adult patients referred to a single centre for liver transplantation.Bone mineral density (BMD) of the lumbar spine and femoral neck were assessed via dual energy X-ray absorptiometry.Demographics,liver disease etiology,medication use and relevant biochemistry were recorded.RESULTS:A total of 117 subjects were included,with low BMD seen in 68.6%,irrespective of disease etiol-ogy.In multivariable analysis,low body mass index (BMI),increased bone turnover and low IGF-1 were independent predictors of low spinal bone density.At the hip,BMI,IGF-1 and vitamin D status were predictive.Despite prevalent elevations of TNFα and IL-6,levels did not correlate with degree of bone loss.The MELD score failed to predict low BMD in this pre-transplant population.CONCLUSION:Osteopenia/osteoporosis is common in advanced liver disease.Low serum IGF-1 is weakly predictive but serum cytokine and MELD score fail to predict the severity of bone disease.     

Insulin-like growth factor binding protein-1 levels in diabetic adolescents and their relationship to metabolic control.

Circulating levels of the low molecular weight insulin-like growth factor binding protein-1 (IGFBP-1) are insulin dependent and vary markedly throughout the day. IGFBP-1 levels are abnormally high in diabetes but the relationship between this and the metabolic status of the patient has not been defined. We have therefore measured fasting IGFBP-1 levels at 0800 h in 32 diabetic adolescents. IGFBP-1 was measured in 19 of these patients after a normal night and in 27 after a night of euglycaemia, maintained with a glucose clamp. In 13 patients both studies were performed and could be compared. Puberty-matched control data were obtained from 69 normal children. In normal prepubertal children IGFBP-1 levels were high; lower levels were found with advancing pubertal development. This fall in IGFBP-1 correlated with pubertal stage (r= 0.68, p less than 0.001) and with fasting insulin levels (r = 0.60, p less than 0.001) which rose with pubertal advancement. In the diabetic children IGFBP-1 levels also correlated inversely with the 0800 h free insulin level but there was no clear relationship with pubertal development. However, when measured after overnight euglycaemia IGFBP-1 levels correlated inversely with pubertal development (r = 0.67, p less than 0.001) as in the normal children. In the patients studied on two comparable occasions the IGFBP-1 level measured after a normal night relative to that measured under standardized euglycaemic conditions was found to correlate closely with the glycosylated haemoglobin level (r = 0.71, p less than 0.005).     

Role of insulin／insulin-like growth factor I signaling pathway in longevity

The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse species including C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly, more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegans to humans. The role of insulin/IGF-1 in longevity is probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood, the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span. In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans, saccharomyces cerevisiae, rodents and humans.     

胰岛素样生长因子基因在非酒精性脂肪变性肝细胞模型中的表达及其意义

目的 研究胰岛素样生长因子-1 (IGF-1)及胰岛素样生长因子结合蛋白-3(IGFBP-3)基因在非酒精性脂肪变性肝细胞模型中的表达变化及其意义. 方法 用油酸诱导永生化人肝细胞(IHH)建立非酒精性脂肪性肝病(NAFLD)细胞模型,油红O染色和细胞内甘油三酯含量检测观察细胞脂肪变情况.IHH细胞分为对照组和NAFLD组,对照组细胞以DMEM/F12培养基培养,NAFLD组给予油酸0.5 mmol/L处理72 h.采用逆转录酶-聚合酶链反应及Western blot和免疫荧光染色方法检测IGF-1和IGFBP-3在两组细胞中的mRNA及蛋白质表达变化.组间均数比较采用t检验. 结果 0.5 mmol/L油酸可成功诱导IHH细胞脂肪变性,油红O染色显示细胞内脂肪滴明显增多,细胞内甘油三酯含量从对照组的(150.2±15.6)μg/ng升高到(275.7±27.2) μg/mg (t=21.67,P＜0.01).油酸诱导后,NAFLD组细胞中IGF-1和IGFBP-3的mRNA相对表达量(分.别为0.76±0.04和1.58±0.93)均较对照组(分别为4.82±1.51和5.41±1.37)明显下降,t值分别为17.915和12.893,P值均＜0.01;IGF-1和IGFBP-3的蛋白质相对表达量(分别为1.00±0.29和0.65±0.36)也较对照组(分别为2.56±0.71和1.23±0.91)明显下降,t值分别为29.17和32.12,P值均＜0.01.免疫荧光染色结果也证实NAFLD组细胞中IGF-1和IGFBP-3的蛋白质表达较对照组明显下降. 结论 非酒精性脂肪变性肝细胞模型的IGF-1和IGFBP-3表达下降,为深入研究临床上部分非酒精性脂肪肝病儿童身高受限的机制提供了实验基础.     

Serum growth hormone and insulin but not insulin-like growth factor-1 levels are elevated in patients with fibromyalgia syndrome

Standard radioimmunoassay (RIA) was employed to quantify basal serum growth hormone (GH), insulin-like growth factor-I (IGF-1), and insulin levels in 32 normoglycemic patients with clinically active fibromyalgia and in 29 normoglycemic control subjects. The GH concentration was significantly higher (P<0.001) in female fibromyalgia patients than age-matched, normal female subjects. In contrast, basal serum IGF-1 concentrations did not differ between these groups. A scatter plot generated from two-stage, least-squares analysis showed that serum GH lacked correlation with the serum IGF-1 concentrations of normal female subjects (P=0.73) and female fibromyalgia patients (P=0.19). In addition to the results from serum GH and IGF-1 RIA, we also found significantly higher fasting serum insulin levels (P=0.03) in male fibromyalgia patients and a trend toward elevated fasting serum insulin levels in the female fibromyalgia population (P=0.07), with the mean fasting level in the male fibromyalgia group (35.7 U/ml^-1) exceeding the upper limit of normal serum insulin levels (i.e., 27 µU/ml^-1). Based on these results, basal serum GH and fasting serum insulin levels appear to be valuable surrogate markers in clinically active, normoglycemic fibromyalgia patients.     

选择性COX-2抑制剂、PGE1对肝硬化大鼠VEGF和CTGF表达的影响

目的探讨环氧合酶-2（COX-2）抑制剂、PGE1对肝硬化大鼠肝脏血管内皮生长因子（VEGF）和结缔组织生长因子（CT-GF）表达的影响。方法用50％CCl4（CCl4／橄榄油：体积比1／1）腹腔注射诱导SD大鼠肝硬化模型,每周2次,共8周。52只SD大鼠随机分为4组：正常对照组（n=10）腹腔注射橄榄油;模型对照组（n=14）,在诱导模型的同时给予等体积生理盐水灌胃,每日1次;选择性COX-2抑制剂罗非昔布组（n=14）,按10mg·kg^-1·d^-1灌胃;米索前列醇即PGE,组（n=14）,按每只大鼠10μg·d^-1灌胃。8周末处死大鼠留取肝组织,通过Westernblot和免疫组织化学方法检测肝组织VEGF和CTGF表达和定位。结果随着CCl4诱导大鼠肝硬化的形成,肝组织VEGF和CTGF的表达增加,与肝硬化模型对照组（安慰剂）比较,选择性COX-2抑制剂罗非昔布能显著降低肝脏VEGF和CTGF蛋白表达水平,而PGE1对VEGF无影响,CTGF显著降低。结论肝纤维化形成过程中,肝组织VEGF和CTGF的表达增加,选择性COX-2抑制罗非昔布能在体内抑制肝组织CTGF和VEGF的表达,这可能是罗非昔布抗肝纤维化的分子机制。     

白蛋白治疗对大鼠脑缺血后血管内皮生长因子和脑水肿的影响

目的研究大鼠脑缺血再灌注后给予人血白蛋白治疗,对脑缺血早期血管内皮生长因子(VEGF)表达和脑水肿及脑梗死体积的影响。方法将40只雄性SD大鼠随机分为假手术组(10只),生理盐水组(15只)和白蛋白组(15只),利用ELISA法分别在大鼠脑缺血6、24、48 h检测血清VEGF蛋白表达水平,免疫组织化学方法观察VEGF表达的空间分布特点。脑切片法测量脑梗死体积,干湿法测量脑组织含水量。结果与生理盐水组比较,白蛋白组大鼠血清VEGF水平在各个时间点明显降低(P<0.05)。VEGF表达主要在梗死区周围的神经元细胞质内。与假手术组比较,生理盐水组和白蛋白组大鼠脑组织含水量明显增加(P<0.05);神经功能缺损评分明显降低(P<0.05)。结论脑缺血早期给予白蛋白治疗后,VEGF高表达下调,脑水肿减轻,神经功能缺损改善。     

转化生长因子β1刺激肝星状细胞中纤溶酶原激活物抑制剂1表达

肝星状细胞(HSC)的激活是肝纤维化发生的中心环节.活化的HSC大量增殖,并合成以胶原为主的细胞外基质(ECM)沉积在肝内.转化生长因子(TGF)β是激活HSC并促进其增殖的最重要细胞因子之一,可促进ECM产生,导致并加速肝纤维化的发生和发展.本实验拟通过免疫细胞化学法检测纤溶酶原激活物抑制剂(PAI)1在HSC中的定位,逆转录聚合酶链反应(RT-PCR)及免疫细胞化学法等研究TGF β1促进PAI 1 mRNA和蛋白质的表达,探讨PAI 1在肝纤维化发生和发展中的作用.