Lung Perfusion Scanning in Hepatic Cirrhosis

Abnormal lung perfusion scans using radioactive particles were found in five out of six cases of hepatic cirrhosis with arterial hypoxaemia. None had clinical evidence of cardiopulmonary disease or signs of pulmonary embolism on arteriography. The scan defects are probably caused by a disorder of the pulmonary microvasculature, which may show regional variation in severity.     

Hepatic Copper Accumulation in Primary Biliary Cirrhosis

Hepatic copper accumulation is a regular feature of primary biliary cirrhosis (PBC). The levels are directly related to the clinical stage of the disease. Since the copper values in PBC are comparable to Wilson''s disease, there is the potential for copper toxicity, although this is speculative since the two diseases differ in the binding, distribution, and intracellular localization of the copper. The involvement of copper toxicity in the progression of PBC is supported by the observation that the highest values occur in association with the hepatic failure that occurs in the advanced stage.Corticosteroid therapy appears to decrease hepatic copper levels in PBC. Although this therapy does not invariably lower the hepatic Cu content in patients with PBC, it does so in many individuals. Therapeutic trials with d-penicillamine are in progress. When results are available they will guide us in the management of individual patients with PBC. In the meantime, dietary copper should be restricted as is done in management of Wilson''s disease.     

肝硬化动物模型造模方法的研究进展

肝硬化(hepatic cirrhosis,HC)是各种慢性肝病发展的晚期阶段,发病初期表现为轻度乏力、腹胀等症状,后期以肝功能损害和门脉高压为主,随病情进一步发展可出现消化道出血、肝性脑病等严重并发症,死亡率极高。然而,目前研究尚未完全明确肝硬化的发病机制。因此,建立肝硬化动物模型,并通过动物实验研究肝硬化的发病机制,探索肝硬化的防治手段是我们需要重视的问题。由于动物与人类种属之间存在巨大差异,若要完全模拟肝硬化的病理特点制备实验动物模型是非常困难的。为深入了解肝硬化的发病机制和特点,本文将对肝硬化动物模型的制备方法进行综述。     

Normal Metallothionein Synthesis in Fibroblasts Obtained from Children with Indian Childhood Cirrhosis or Copper-Associated Childhood Cirrhosis

We previously demonstrated decreased metallothionein (MT) synthesis in cultured fibroblasts obtained from an American boy with findings typical of Indian Childhood Cirrhosis (ICC). We now report normal basal, copper-induced, and zinc-induced MT synthesis in the fibroblasts of two Indian boys and one Irish boy with typical ICC and one Indian boy with copper-associated childhood cirrhosis. This suggests that etiologies other than impaired MT production should be sought as the primary defect in these disorders.     

Whole-Body and Hepatic Insulin Resistance in Obese Children

Background

Insulin resistance may be assessed as whole body or hepatic.

Objective

To study factors associated with both types of insulin resistance.

Methods

Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (<6.67 ng/ml). We determined metabolite and hormone levels and performed a liver ultrasound.

Results

The majority, 73.1%, of obese children had whole-body insulin resistance and hepatic insulin resistance, while 7% did not have either type. HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother''s BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver.

Conclusion

In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance.     

超声造影在肝硬化合并肝内局灶性小病灶中的诊断价值

目的:探讨超声造影(CEUS)在肝硬化合并肝内局灶性小病灶(≤3.0 cm)中的诊断价值。方法:选择我院自2010年4月至2014年8月患有肝硬化合并肝内局灶性小病灶的患者100例,采用MRI、CT及病理确定病灶良恶性,同时对比影像结果,计算常规超声和CEUS的准确性。结果:MRI、CT及病理确定病灶105个,其中恶性组45例,良性组60例,超声造影技术能清晰的显示出血流灌注的情况以及动脉相、门脉相及延迟相的特点。数据统计结果显示常规超声和CEUS的准确性、特异性和敏感性分别为59.05%、77.78%、45.00%和95.24%、95.56%、95.00%,两者之间的差异具有统计学意义(P0.05)。结论:相对于常规超声,CEUS对患有肝硬化合并肝内局灶性小病灶的患者具有更高的诊断价值。     

骨髓干细胞移植治疗肝硬化的基础与临床研究现状

肝硬化是一种临床常见的肝病良性终末期表现。目前临床上尚缺乏有效的治疗措施。肝脏移植是最理想的治疗方法,但受供体肝脏来源限制,且费用昂贵。近年来开展的自体骨髓干细胞(BMSCs)移植治疗,为肝硬化的治疗带来了新的希望。BMSCs主要包括造型血干细胞和间充质干细胞,其具有可塑性,体外通过生长因子,体内利用特定微环境均可诱导BMSCs分化为肝前体细胞和成熟肝细胞,并明显改善肝功能。从动物实验到临床研究亦表明,BMSCs具有来源丰富、费用低廉、损伤小、自体移植不栓塞、无排斥反应等优点,为治疗肝病带来了新思路,有望成为生物人工肝的细胞来源。本文就BMSCs移植治疗肝硬化的研究现状,尤其是移植途径以及在肝脏内定居、迁移和分化机制的示踪观察方法和存在的问题作一综述,以期为从事肝病研究的同仁提供参考依据。通过对BMSCs移植从基础研究及临床应用的最新进展的描述,展示BMSCs在肝硬化治疗方面良好的治疗前景。     

Hepatic Arterial Vasodilation Is Independent of Portal Hypertension in Early Stages of Cirrhosis

Introduction

The compensatory increase in hepatic arterial flow with a decrease in portal venous flow is known as the hepatic arterial buffer response. In cirrhosis with elevated portal pressure, the vascular resistance of the hepatic artery is decreased. Whether this lower resistance of the hepatic artery is a consequence of portal hypertension or not remains unknown.

Study Aim

The aim of the study was to investigate the hepatic arterial resistance and response to vasoconstriction in cirrhosis without portal hypertension (normal portal resistance).

Methods

Cirrhosis was induced by CCl₄-inhalation for 8 weeks (8W, normal portal resistance) and for 12–14 weeks (12W, elevated portal resistance). Bivascular liver perfusion was performed at 8W or 12W and dose response curves of methoxamine were obtained in the presence or absence of LNMMA (nitric oxide synthase blocker). Vascular resistances of the hepatic artery (HAR), portal vein (PVR) and sinusoids (SVR) were measured. Western Blot (WB) and Immunohistochemistry (IHC) were done to measure eNOS and HIF 1a expression.

Results

HAR in both groups of cirrhotic animals (8W and 12W) were lower compared to controls. Dose response curves to methoxamine revealed lower HAR in both cirrhotic models (8W and 12W) regardless the magnitude of portal resistance. LNMMA corrected the dose response curves in cirrhosis (8W and 12W) to control. WB and IHC show increased protein expression of eNOS and HIF1a in 8W and 12W.

Conclusion

Hepatic arterial resistance is decreased in cirrhosis independent of portal resistance. Vasodilation of the hepatic artery in cirrhosis seems to be influenced by hypoxia rather than increase in portal resistance. Nitric oxide is the main vasodilator.     

Serum Sphingolipid Variations Associate with Hepatic Decompensation and Survival in Patients with Cirrhosis

Background

Sphingolipids constitute bioactive molecules with functional implications in liver homeostasis. Particularly, ablation of very long chain ceramides in a knockout mouse model has been shown to cause a severe hepatopathy.

Methods

We aimed to evaluate the serum sphingolipid profile of 244 patients with cirrhosis prospectively followed for a median period of 228±217 days via mass spectrometry.

Results

We thereby observed a significant decrease of long and very long chain ceramides, particularly of C24ceramide, in patients with increasing severity of cirrhosis (p<0.001). Additionally, hydropic decompensation, defined by clinical presentation of ascites formation, was significantly correlated to low C24ceramide levels (p<0.001) while a significant association to hepatic decompensation and poor overall survival was observed for low serum concentrations of C24ceramide (p<0.001) as well. Multivariate analysis further identified low serum C24ceramide to be independently associated to overall survival (standard beta = -0.001, p = 0.022).

Conclusions

In our current analysis serum levels of very long chain ceramides show a significant reciprocal correlation to disease severity and hepatic decompensation and are independently associated with overall survival in patients with cirrhosis. Serum sphingolipid metabolites and particularly C24ceramide may constitute novel molecular targets of disease severity, hepatic decompensation and overall prognosis in cirrhosis and should be further evaluated in basic research studies.     

Coffee Consumption Decreases Risks for Hepatic Fibrosis and Cirrhosis: A Meta-Analysis

Background and Aim

Previous studies have demonstrated that coffee consumption may be inversely correlated with hepatic fibrosis and cirrhosis. However, the reported results have been inconsistent. To summarize previous evidences quantitatively, a meta-analysis was performed.

Methods

The Medline, Web of Science, and Embase databases (from inception to June 2015) were searched to identify relevant trials that evaluated the effects of coffee consumption on hepatic fibrosis or cirrhosis. Odds ratios (ORs) of advanced hepatic fibrosis or cirrhosis for low or moderate, high, and any coffee consumption versus no consumption were pooled. Two cups per day was used as the cut-off level between low or moderate and high consumption.

Results

Sixteen studies were included, involving 3034 coffee consumers and 132076 people who do not consume coffee. The pooled results of the meta-analysis indicated that coffee consumers were less likely to develop cirrhosis compared with those who do not consume coffee, with a summary OR of 0.61 (95%CI: 0.45–0.84). For low or moderate coffee consumption versus no consumption, the pooled OR of hepatic cirrhosis was 0.66 (95%CI: 0.47–0.92). High coffee consumption could also significantly reduce the risk for hepatic cirrhosis when compared with no coffee consumption (OR = 0.53, 95%CI: 0.42–0.68). The effect of coffee consumption on hepatic fibrosis was summarized as well. The pooled OR of advanced hepatic fibrosis for coffee consumption versus no consumption was 0.73 (95%CI: 0.58–0.92). The protective effect of coffee on hepatic fibrosis and cirrhosis was also identified in subgroup meta-analyses of patients with alcoholic liver disease and chronic hepatitis C virus (HCV) infection.

Conclusion

Coffee consumption can significantly reduce the risk for hepatic fibrosis and cirrhosis.     

Modulation of the Metabiome by Rifaximin in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE.

Methods

Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin.

Results

There was a significant improvement in cognition(six of seven tests improved,p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar.

Conclusions

Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01069133","term_id":"NCT01069133"}}NCT01069133