肝硬化逆转问题的思考:狭义与广义

正随着慢性乙型肝炎(CHB)/慢性丙型肝炎(CHC)抗病毒治疗的进展,对肝纤维化(包括早期肝硬化)病理组织学的可逆性及失代偿期肝硬化患者的肝功能改善的研究翻开了新篇章。2015年美国肝脏病研究会(AASLD)在芝加哥召开了"Emerging Trends Conferene Targets Antifibrotic Drug Trials:Strategies and Endpoints"研讨会,昭示抗肝纤维化研究到了重要的转变     

瞬时弹性成像技术诊断肝纤维化专家意见

基于肝脏瞬时弹性成像技术(transient elastography,TE)的Fibroscan能够通过检测肝脏硬度值(liver stiffness measurement,LSM)来判断肝纤维化,TE诊断肝炎肝硬化的效能优于FibroTest、 FibroMeter、 HepaScore、APRI、API、FIB-4、Forns指数、Hui指数、代偿性肝硬化指数(CCD等血清生物学标志物[1-7],在我国已被批准用于临床.为促进这一技术在临床上的正确合理应用,中国肝炎防治基金会组织专家撰写了《瞬时弹性成像技术诊断肝纤维化专家意见》,并在郑州召开讨论会进一步修改、定稿.随着临床实践的进展及证据积累,专家委员会将对本意见作进一步完善.     

实时剪切波弹性成像检测肝脏硬度与血清肝纤维化指标及其与肝脏病理的相关性

目的:探讨实时剪切波弹性成像(supersonic shear imaging,SSI)测得肝脏硬度与血清肝纤维化指标及肝脏病理的相关性.方法:选取郑州大学第一附属医院2011-05/2012-07诊断为"自身免疫性肝病"患者70例,均进行血清肝纤维化指标检测,肝脏活检和SSI检测.分析肝脏硬度与血清肝纤维化指标及肝脏病理的相关性.结果:(1)肝脏硬度与肝组织炎症分级及纤维化分期有显著相关性(45.45,20.18,21.21,13.60vs15.18;19.33,37.29vs14.49;均P<0.05),相关系数为0.584和0.541;(2)肝脏硬度与Ⅲ型前胶原、Ⅳ型胶原、层粘蛋白、透明质酸均有显著相关性(12.02±8.55vs6.96±2.27;97.96±27.89vs78.67±25.57;306.78±208.48vs46.14±41.23;257.42±124.51vs88.05±15.08;P<0.05),相关系数为0.339,0.365,0.409和0.450;(3)肝组织炎症分级与纤维化分期有显著相关性(r=0.616,P<0.01).结论:SSI测得肝脏硬度与血清肝纤维化指标及肝脏病理有较好的相关性,SSI可动态监测肝纤维化进展,评估肝纤维化程度.     

慢性乙型肝炎抗病毒治疗10年预后及其影响因素

目的探讨慢性乙型肝炎进行抗病毒治疗10年后病情预后及其影响因素。方法选取2008年1月至2008年12月北京地坛医院住院慢性乙型肝炎患者152例作为研究对象,治疗10年后截至2018年12月将发生肝硬化患者34例设为病例组,而未发生肝硬化患者118例设为对照组。对比两组患者基本情况、各项化验指标、乙肝病毒载量及肝脏病理等结果,分析肝硬化发生相关的影响因素。结果单因素分析结果显示,患者的年龄、饮酒史、血小板、脾脏厚度、门静脉宽度、终点HBV DNA与肝硬化形成存在相关性(P0.05)。通过Kaplan-Meier法生存分析显示,随着肝脏病理炎症及纤维化程度加重,肝硬化发生率升高(χ~2=18.749,P0.001;χ~2=33.214,P0.001)。通过Cox回归进行多因素分析,患者年龄、饮酒史、肝脏纤维化分期及终点HBV DNA水平等因素是肝硬化发生的危险因素。结论慢性乙型肝炎患者的年龄、饮酒史、纤维化分期及终点HBV DNA水平等因素是发生肝硬化的独立危险因素,与肝硬化发生具有密切相关性。     

2012年肝纤维化领域的研究进展

肝纤维化是各类损伤因子累及肝脏后的一种病理修复状态,肝纤维化甚至肝硬化能否改善乃至逆转是目前肝纤维化研究领域的关键.以往的动物模型已证实肝纤维化的逆转,但临床领域缺乏详尽充分的数据为此提供依据.令人鼓舞的是,近期越来越多的研究支持人体中肝纤维化甚至肝硬化的转归.2012年12月份Lancet发表的一篇随机双盲对照研究显示,富马酸替诺福韦酯治疗慢性乙型肝炎(CHB)患者,能够实现肝纤维化和肝硬化的逆转[1].该研究旨在评估对于CHB患者采用富马酸替诺福韦酯治疗在5年内对肝纤维化和肝硬化的疗效,在完成为期48周的随机双盲比较富马酸替诺福韦酯和阿德福韦酯后,研究者将符合条件的受试者(HBeAg阳性或阴性)纳入了为期7年的富马酸替诺福韦酯的开放研究,在第240周时再次进行肝脏活组织病理学检查,主要评估肝脏组织学改善程度(Knodell坏死炎症评分≥2且纤维化程度未加重)以及肝纤维化的逆转情况(Ishak评分降低≥1单位).治疗基线时28％的患者存在肝硬化(Ishak评分5分或6分),而74％肝硬化患者治疗后评分降低≥1单位,肝硬化消失;入组时未患肝硬化的252名患者中仅有3名在5年内进展为肝硬化;87％随机治疗的患者组织学改善,且51％的患者在第240周时肝纤维化出现逆转.     

对肝硬化认识的改变与部分研究重点

<正>肝硬化(cirrhosis)原于希腊字根"黄褐色",200多年来,对肝硬化的概念认识主要依据其形态学特征——肝组织结节,这些结节由增生肝细胞与纤维间隔组成,并伴有肝血管改建与组织重构,1977年WHO也将肝硬化定义为"弥漫性肝脏纤维化与异常结节形成"。多年来,肝硬化作为后期或终末期肝病的代名词,一直影响着我们对慢性肝病病理机制、临床诊治的认识及其预后判断。事实上,肝硬化不是一个独立的疾病,而是多种慢性肝病的共同病理结局[1],是引起人类因疾病死亡的第6～12位原因。近年来,随肝纤维化病理生理     

莫迪司、普美显增强磁共振与肝纤维化分期的相关性研究

肝硬化的严重程度与临床治疗密切相关,因此,对肝纤维化进行准确分期尤为重要.穿刺活检虽然能对肝硬化程度进行准确分期,因其为有创检查,在临床应用中有一定的限制.临床磁共振(magnetic resonance image,MRI)检查已常规用于肝脏疾病的诊断.近年来,两种新型对比剂莫迪司和普美显已成功用于肝脏成像,可以无创地用于肝纤维化分期以及肝功能的评估,肝功能不同程度的肝硬化患者的肝实质强化程度具有统计学差异.本文将近十年来莫迪司、普美显增强MRI用于评估肝纤维化分期的研究现状与进展进行简要综述.     

从最新指南看中医药治疗肝硬化腹水的研究策略

正最近,中华医学会肝病学分会发布《肝硬化腹水及相关并发症的诊疗指南》[1],并对肝硬化腹水及其相关并发症的诊疗提出了26条推荐意见,有助于临床医生在肝硬化腹水的诊疗过程中做出合理决策。2017年7月,中华中医药学会脾胃病分会发布《肝硬化腹水中医诊疗专家共识意见(2017)》[2],对该学会2012年公布的《肝硬化腹水中医诊疗规范专家共识意见》[3]进行了更新。随着中医药防治肝硬化腹水研究的深入开展,人们     

临床前代偿期肝硬化中医证候要素及其与肝组织分级分期评分的相关性研究

目的:探究按临床诊断标准尚不够条件但根据肝硬化诊断的"金标准"可以确诊为肝硬化患者的中医证候要素及其与肝组织分级分期评分的相关性,以充实肝硬化的中医证候理论。方法:通过流行病学横断面调查的方法对25例研究对象的中医证候要素及其与肝脏大体形态学改变(腹腔镜或开腹手术直视下观察)、肝组织分级分期评分的相关性进行描述性分析。结果:①肝脏大体形态改变在各证候要素中具体分布为:瘀(76.0%)>郁(72.0%)>脾虚(60.0%)>湿(48.0%)>热(36.0%)>阴虚(4.0%)>阳虚(0%)=其他证候要素(0%)=无证可辨(0%);②肝脏组织炎症程度分级多分布在G1、G2,瘀以G1、G2为主(G1占52.6%,G2占31.6%),郁以G1为主(占61.1%);③肝脏纤维化程度分期主要为S4,部分未达到S4(即组织学诊断尚不能确立肝硬化);在证候要素瘀中S4占78.9%,在证候要素郁中S4占72.2%;④此期患者肝脏大体形态学改变80.0%为小结节。结论:本研究中,①临床前代偿期肝硬化患者的中医证候要素分布以瘀、郁为主,G1、G2为其主要的肝脏炎症程度分级评分,S4为其主要肝脏纤维化程度分期评分,亦见部分未达到S4,小结节为其主要大体形态改变;②此组患者肝组织学活检诊断肝硬化存在一定的漏诊率(28.0%)。     

原发性胆汁性肝硬化肝纤维化无创诊断的研究进展

原发性胆汁性肝硬化（PBC）是一种慢性肝内胆汁淤积性疾病,最终可发生肝硬化和（或）门脉高压。目前,肝脏活检是对PBC进行组织学分期的＂金标准＂,组织学分期较高者应用熊去氧胆酸（UDCA）的疗效降低,病死率增加。但是,由于肝脏活检属于创伤性操作,难以反复多次进行,并且存在取样误差、不同病理阅片者判断的个体差异等缺点[1],所以,研究无创性指标或手段辅助诊断肝纤维化具有重要的意义。现对PBC肝纤维化无创诊断的研究进展做一综述。     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.