Neurovascular relationships in the wall of the stomach during interference with the portal blood flow

Summary The author examined the intestinal wall in 5 cadavers of patients deceased from cirrhosis and in 20 animals (cats and dogs) after the ligature of their portal veins. Tissues were treated by Bielschowsky-Gros method with an additional staining of the blood vessels by acid fuchsin. Intimate neurovascular relations were revealed in the liver both in human cirrhosis and in experimental animals (dogs) after the ligature of the portal vein. These relations were represented by the presence of terminations of dendritis of the ganglionic cells on capillaries. Large numbers of synaptic endings of thin fibers (of various length) were also found on the blood vessels.Presented by Active Member of the AMN SSSR V. N. Chernigovskii     

Collagen and fibronectin of the liver in children with congenital fibrosis, an extrahepatic portal circulation block and post-hepatitis cirrhosis (an immunohistochemical study)

Immunofluorescence techniques were used to examine the distribution of Types I, III, IV and V collagen and fibronectin in the liver biopsy specimens from children with congenital liver fibrosis (CLF), extrahepatic portal blood circulation block, and cirrhosis developed following viral hepatitis. Both common patterns and characteristic features of the development of sclerotic processes were established. The common feature is the development of periportal connective tissue (CT) fibrosis mainly at the expense of Types I, III and V collagen and the accumulation of Types I, III, IV, V collagen and fibronectin in the walls of sinusoids during their "collagenization". The distinctive characteristic of posthepatic cirrhosis is the location of fibronectin and Type IV collagen in fibrous CT. Characteristic of CLF is high fibronectin concentrations in the areas of CT neoplasms along the periphery of portal tracts.     

The portal vein as a distinct immunological compartment – A comprehensive immune phenotyping study

Advanced liver diseases are associated with impaired intestinal barrier function, which results in bacterial influx via the portal vein to the liver, causing hepatic and systemic inflammation. Little is known about possible concomitant trafficking of immune cells from the intestines to the liver. We therefore performed a comprehensive immunophenotyping study of the portal venous versus peripheral blood compartment in patients with liver cirrhosis who received a transjugular intrahepatic portosystemic stent shunt (TIPS). Our analysis suggests that the portal vein constitutes a distinct immunological compartment resembling that of the intestines, at least in patients with advanced liver cirrhosis. In detail, significantly lower frequencies of naïve CD4⁺ T cells, monocytes, dendritic cells and Vδ2 T cells were observed in the portal vein, whereas frequencies of activated CD4⁺ and CD8⁺ T cells, as well as of mucosa-associated Vδ1 T cells were significantly higher in portal venous compared to peripheral blood. In conclusion, our data raises interesting questions, e.g. whether liver cirrhosis-associated chronic inflammation of the intestines and portal hypertension promote an influx of activated intestinal immune cells like γδ T cells into the liver.     

Pathology of septum formation in primary biliary cirrhosis: A histological study in the non-cirrhotic stage

Summary Bridging or incomplete septum formation, an important step leading to cirrhosis in various chronic progressive liver diseases, was examined in 231 liver biopsy specimens of primary biliary cirrhosis (non-cirrhotic stage). Incomplete septa from the enlarged portal tracts and portal to portal bridges were frequent and appeared first, while portal to central ones appeared subsequently and became frequent in the liver specimens with changes resembling cirrhosis. These septa were divided into four types histologically: ductular, lymphocytic, loose connective tissue and fibrous type. More than one type was usually found in the same specimen. The pathology of the first three types was similar to and frequently continuous with that of neighbouring periportal regions, suggesting that most of these septa were formed by the extension of periportal destructive processes. The fibrous type might be an advanced form of the other three types. Incomplete septa seemed to pinch off part of the hepatic parenchyma in a hepatic lobule; this was followed by an unusual enlargement of the portal tracts and an approximation of portal tracts and central veins. There were perivenular hepatocellular necroses on occasion. Progression of periportal hepatocellular damage may lead to septum formation and finally progress to cirrhosis, in primary biliary cirrhosis. The significance of perivenular necroses remains speculative.     

Autologous bone marrow cells in the treatment of cirrhosis of the liver

The data characterizing tolerance and efficiency of autologous bone marrow cells in the treatment of patients with cirrhosis of the liver are presented. Injection of autologous bone marrow cells was not associated with the development of adverse reactions. Cell therapy of patients with compensated cirrhosis arrested asthenic syndrome, reduced cytolysis, increased the level of serum albumin and platelet count. Ultrasonic examination revealed reduction of portal hypertension (the area of the spleen and the portal vein lumen decreased). In patients with decompensated cirrhosis, a positive response presenting as reduction of the disease severity (by 1.9 points) was observed in 48.6% cases. Positive shifts in these patients were associated with a decrease of ALT and AST levels, reduction of laboratory signs of cirrhosis, increase in platelet count, and reduction of the asthenic syndrome. Hence, therapy with autologous bone marrow cells is safe and, according to preliminary results, can be regarded as a new approach to the treatment of patients with cirrhosis of the liver. __________ Translated from Kletochnye Tehnologii v Biologii i Medicine, No. 4, pp. 231–237, October, 2007     

肝窦内皮细胞损伤和表型改变在大鼠肝硬化门脉高压发生中的作用

目的：探讨肝窦内皮细胞（SECs）损伤和表型改变与大鼠肝硬化门脉高压的关系。 方法： 采用二甲基亚硝胺（DMN）4周12次腹腔注射复制大鼠肝硬化模型，分别于造模后1 d、2 d、3 d、1周、2周、4周、6周、8周作动态观察；肠系膜前静脉分支插管法测门脉压力（Ppv）；透射电镜观察肝组织超微结构；免疫组化观察肝窦壁CD44和Ⅷ因子相关抗原（vWF）表达；Northern blot检测肝组织内皮素-1（ET-1） mRNA和内皮型一氧化氮合酶（eNOS）mRNA 表达；Western blot检测肝组织eNOS表达；放射免疫法测定血清透明质酸（HA）和肝组织ET-1含量。 结果： DMN造模1 d后CD44染色明显弱于正常对照组（P<0.05），SECs窗孔减少，血清HA含量显著高于正常对照组(P<0.05)；DMN造模2 d后vWF阳性染色明显强于正常对照组(P<0.05)；DMN大鼠的Ppv与肝窦壁vWF表达量和血清HA含量呈显著正相关(P<0.05)；造模2 d和3 d时ET-1 mRNA表达强于正常对照组，ET-1含量轻度高于正常对照组；造模1 d、2 d和3 d时eNOS mRNA表达强于正常对照组，而eNOS一直呈低水平状态。 结论：SECs损伤和表型改变是DMN大鼠肝硬化门脉高压形成的病理基础之一；ET-1和NO产生的平衡失调，使肝内血流阻力增加，在门脉高压形成过程中起重要作用。     

DISTRIBUTION OF COLLAGEN TYPES I, III, AND V IN FIBROTIC AND NEOPLASTIC HUMAN LIVER

The distribution of collagen types I, III, and V in normal and fibrotic human livers and hepatocellular carcinoma was studied by indirect immunofluorescence procedure using type specific antibodies. Type I collagen as well as type III collagen was present in normal liver within the portal tracts and along the perisinusoidal spaces. Basement membrane collagen, type V collagen, was demonstrated only around the bile ducts and vessels of the portal tracts and central veins. In fibrotic liver, both type I and III collagens were found in increased amounts in fibrotic areas. In fibrous septa of active cirrhosis, however, type I collagen as well as type III collagen was abundant, whereas in inactive cirrhosis type I fibers were predominant. Type V collagen was observed in the walls of proliferative bile ductules and vessels in the fibrotic liver, and also along the sinusoids in the periportal areas. In hepatocellular carcinoma, each type of collagen was distributed regularly along the sinusoid-like vascular channels within the tumor.     

The usefulness of non-invasive liver stiffness measurements in predicting clinically significant portal hypertension in cirrhotic patients: Korean data

Background/Aims

Liver stiffness measurement (LSM) has been proposed as a non-invasive method for estimating the severity of fibrosis and the complications of cirrhosis. Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence of portal hypertension, but its invasiveness limits its clinical application. In this study we evaluated the relationship between LSM and HVPG, and the predictive value of LSM for clinically significant portal hypertension (CSPH) and severe portal hypertension in cirrhosis.

Methods

LSM was performed with transient elastography in 59 consecutive cirrhotic patients who underwent hemodynamic HVPG investigations. CSPH and severe portal hypertension were defined as HVPG ≥10 and ≥12 mmHg, respectively. Linear regression analysis was performed to evaluate the relationship between LSM and HVPG. Diagnostic values were analyzed based on receiver operating characteristic (ROC) curves.

Results

A strong positive correlation between LSM and HVPG was observed in the overall population (r²=0.496, P<0.0001). The area under the ROC curve (AUROC) for the prediction of CSPH (HVPG ≥10 mmHg) was 0.851, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for an LSM cutoff value of 21.95 kPa were 82.5%, 73.7%, 86.8%, and 66.7%, respectively. The AUROC at prediction of severe portal hypertension (HVPG ≥12 mmHg) was 0.877, and the sensitivity, specificity, PPV, and NPV at LSM cutoff value of 24.25 kPa were 82.9%, 70.8%, 80.6%, and 73.9%, respectively.

Conclusions

LSM exhibited a significant correlation with HVPG in patients with cirrhosis. LSM could be a non-invasive method for predicting CSPH and severe portal hypertension in Korean patients with liver cirrhosis.     

法莫替丁对肝硬化大鼠肝门阻断时胃粘膜的保护作用

目的：探讨法莫替丁对肝门阻断所致的肝硬化大鼠胃粘膜损伤的影响及其机制。 方法： 雄性Wistar大鼠50只，随机分为5组，每组10只;A组为健康未行肝门阻断对照组；B组为健康大鼠行肝门阻断组；C组为肝硬化未行肝门阻断组；D组为肝硬化行肝门阻断组；E组为肝硬化行肝门阻断+法莫替丁保护组。E组在手术前从尾静脉注入80 mg/kg体重的法莫替丁，而其余各组以等量生理盐水替代。观察各组的胃液pH、胃结合粘液量、胃粘膜血流及胃粘膜损伤指数。 结果： B组与A组比较，各指标差异无显著(P>0.05)；C组、D组和E组的胃液pH和胃结合粘液量明显低于A组(P<0.05)，胃粘膜血流也明显少于A组(P<0.01),损伤指数明显大于A组(P<0.01)；且D组各指标的变化均较C组明显(P<0.01)；而E组与C组相比，差异无显著(P>0.05)。 结论： 肝门阻断可引起肝硬化大鼠胃粘膜损伤的加重，法莫替丁可能通过改善胃粘膜的微循环而对肝硬化大鼠胃粘膜起保护作用。     

Portal and splanchnic hemodynamics after partial splenic embolization in cirrhotic patients with hypersplenism

To assess the acute effects of partial splenic embolization (PSE) on portal and splanchnic hemodynamics in patients with cirrhosis. Ninety‐five patients with hypersplenism were included in the study. Duplex examinations were performed before and 3 and 7 days after PSE. Portal and splanchnic hemodynamics including vessel cross‐sectional area (CSA), mean flow velocities (cm/s), blood flows (mL/min), Doppler indices as portal congestion index (CI), liver vascular index, hepatic artery and superior mesenteric artery (SMA) pulsatility and resistive indices (PI and RI), were performed before and after PSE. In our study, 69 of 95 patients were males (72.6%) and 26 females (27.3%). Chronic hepatitis C virus infection was the main cause of cirrhosis (81.1%). PSE failed technically in six patients (6.3%). After PSE, both CSA and CI significantly decreased (p < 0.05 and <0.01). The portal vein velocity significantly increased (p < 0.01). The portal flow volume (892.4 ± 151 mL/min) did not show significant changes. The hepatic artery RI and PI showed a steady increase that became significant 7 days post‐PSE (p < 0.05). The RI and PI of SMA increased significantly after 7 days of PSE (p < 0.05). PSE has an immediate portal decompression effect in patients with portal hypertension without reduction in portal flow. This effect on portal pressure should be investigated in future studies as a potential tool for management of acute variceal bleeding when other medical procedures fail.     

内源性硫化氢对实验性肝硬化门静脉高压的影响及其与一氧化氮的相互作用

目的：探讨硫化氢（ H2 S）对实验性肝硬化门静脉高压的影响及H2 S与一氧化氮（ NO）的相互作用。方法：将32只雌性SD大鼠,随机分为肝硬化组、肝硬化＋炔丙基甘氨酸（ PPG）组、肝硬化＋硫氢化钠（ NaHS）组和正常组4组,每组8只。肝硬化组、肝硬化＋PPG组及肝硬化＋NaHS组大鼠采用四氯化碳（CCl4）复合法制备肝硬化门静脉高压动物模型。造模结束第2天,肝硬化＋PPG组大鼠腹腔注射PPG 30 mg/（kg．d）,肝硬化＋NaHS组大鼠腹腔注射NaHS 56μmol/（kg．d）,肝硬化组及正常组大鼠腹腔给予10 ml/（ kg．d）生理盐水。给药干预1周后,测定各组大鼠门静脉压力（ PVP）、大鼠门静脉血浆H2 S、NO含量。结果：实验结束,经病理学观察证实肝硬化大鼠模型制备成功,PVP均大于11．80 mmHg,显示门静脉高压形成。肝硬化组、肝硬化＋PPG组和肝硬化＋NaHS组PVP和门静脉血浆NO含量均高于正常组,门静脉血浆H2S含量均低于正常组（P＜0．05）。肝硬化＋PPG组PVP和门静脉血浆NO含量高于肝硬化组,门静脉血浆H2 S含量低于肝硬化组;肝硬化＋NaHS组PVP和门静脉血浆NO含量低于肝硬化组,门静脉血浆H2S含量高于肝硬化组（P＜0．05）。结论：内源性H2S对肝硬化门静脉高压发挥保护性调节作用。内源性H2 S与NO在肝硬化门静脉高压形成中可能呈现相互的负性调节作用,共同参与肝硬化门静脉高压形成的调控机制。     

The cut-off value of transient elastography to the value of hepatic venous pressure gradient in alcoholic cirrhosis

Background/AimsThe hepatic venous pressure gradient (HVPG) reflects portal hypertension, but its measurement is invasive. Transient elastography (TE) is a noninvasive method for evaluating liver stiffness (LS). We investigated the correlation between the value of LS, LS to platelet ratio (LPR), LS-spleen diameter-to-platelet ratio score (LSPS) and HVPG according to the etiology of cirrhosis, especially focused on alcoholic cirrhosis.MethodsBetween January 2008 and March 2017, 556 patients who underwent HVPG and TE were consecutively enrolled. We evaluated LS, LPR, and LSPS according to the etiology of cirrhosis and analyzed their correlations with HVPG.ResultsThe LS value was higher in patients with alcoholic cirrhosis than viral cirrhosis based on the HVPG (43.5 vs. 32.0 kPa, P<0.001). There were no significant differences in the LPR or LSPS between alcoholic and viral cirrhosis groups, and the areas under the curves for the LPR and LSPS in subgroups according to HVPG levels were not superior to that for LS. In alcoholic cirrhosis, the LS cutoff value for predicting an HVPG ≥10 mmHg was 32.2 kPa with positive predictive value (PPV) of 94.5% and 36.6 kPa for HVPG ≥12 mmHg with PPV of 91.0%.ConclusionsThe LS cutoff value should be determined separately for patients with alcoholic and viral cirrhosis. In alcoholic cirrhosis, the LS cutoff values were 32.2 and 36.6 kPa for predicting an HVPG ≥10 and ≥12 mmHg, respectively. However, there were no significant differences in the LPR or LSPS between alcoholic and viral cirrhosis groups.     

一氧化氮合酶2A基因启动子-969(G→C)多态性与肝硬化门静脉高压的相关性

目的探讨一氧化氮合酶2A(nitricoxidesynthase2A,NOS2A)基因启动子-969(G→C)多态性与肝硬化门静脉高压的相关性。方法采用病例对照和聚合酶链反应-限制性片段长度多态性技术,检测106例乙肝后肝硬化患者和108名健康对照者NOS2A基因启动子-969(G→C)多态性,比较等位基因及基因型频率;应用逆转录-聚合酶链反应和Western印迹技术,检测肝硬化组织NOS2AmRNA和蛋白表达。构建NOS2A基因启动子-969(G→C)多态性荧光素酶重组质粒,瞬时转染,分析多态性的功能。结果在门静脉高压症组C等位基因和GC基因型频率为16.9%、33.8%,比正常对照组高(8.8%、17.6%),差异有显著性(P<0.05,OR=2.42),相关分析呈正相关(r=0.18)。单纯肝硬化组与对照组的C等位基因和GC基因型频率相比,差异无显著性(P>0.05)。C等位基因携带者比G等位基因携带者肝硬化组织NOS2AmRNA及蛋白表达明显增强,GC基因型启动子的活性显著升高。Logistic多元逻辑回归分析显示这一多态性是形成门静脉高压症新的独立危险因素。结论NOS2A基因启动子-969(G→C)多态性与门静脉高压症相关,导致启动子活性增强,是形成门静脉高压症的新的危险因素。     

The morphology and morphogenesis of alcoholic cirrhosis of the liver]

A total of 42 biopsy specimens of the liver (blind and spot) in 32 patients with alcoholic cirrhosis of the liver were investigated. Morphological, portal, postnecrotic, and mixed types of cirrhosis were established. The portal type of cirrhosis is most common. On the basis of repeated analyses of biopsy materials of the liver it may be assumed that the development of cirrhosis of the liver of alcoholic etiology is connected with multiple attacks of acute alcoholic hepatitis. Abstention from alcohol consumption resulted in stifestations of exacerbation of cirrhosis. On the other hand, continuation of alcohol consumption contributed to progressing of cirrhosis, which following several attacks of alcoholic hepatitis, may change its morphological type: portal cirrhosis "transforms" into the postnecrotic or mixed type. The data obtained clarified the role of ethanol in progressing alcoholic cirrhosis of the liver, which according to the initial mecranisms of its development in postnecrotic, since every attack of acute alcoholic hepatitis is accompanied by coagulative (fields of alcoholic hyaline, or Mallory's bodies), or by colliquative (balloon dystrophy) necrosis of hepacytes.     

Hepatic microcirculation of liver cirrhosis studied by corrosion cast/scanning electron microscope examination

Changes of hepatic microcirculations in 22 autopsy cases of liver cirrhosis were analyzed by corrosion cast/scanning electron microscope (SEM) examination. By this method, the site of arterioportal (A-P) communication in liver cirrhosis was clearly demonstrated between proliferated portal venules and arterial capillaries. The communications were observed at the same site as in the normal liver and were not at larger arterial and portal vein branches. The findings indicate that the increase of A-P communication in liver cirrhosis may be called "capillary shunting". On the basis of the findings, it was postulated that the A-P shunt could not assist in the development of portal hypertension by the transmission of high arterial pressure to the portal vein but could only compensate for decreased portal flow and/or elevate the oxygen concentration in the sinusoids to improve the hypoxic state of the liver parenchyma. It was also demonstrated that the arterial capillarization of the interstitial septa in micronodular wide septal cirrhosis was more prominent than that in macronodular thin septal cirrhosis. A grade of portal vein reduction and compensatory arterialization in a fibrous septum have been regarded as an index to estimate the advancement of liver cirrhosis. Therefore, if alcoholic micronodular cirrhosis could change into macronodular, the process should have occurred at least before the establishment of micronodular wide septal cirrhosis.     

Increased sinusoidal resistance is responsible for the basal state and endothelin-induced venoconstriction in perfused cirrhotic rat liver

The localization of increased intrahepatic vascular resistance and the segmental vascular responsiveness to endothelin-1 are not well known in liver cirrhosis. We determined the segmental vascular resistances and their response to endothelin-1 of isolated portally perfused bile duct ligation (BDL)-induced cirrhotic rat livers. The portal occlusion pressure (Ppo) and the hepatic venous occlusion pressure (Phvo) were obtained by analyzing the profiles of the portal (Ppv) and hepatic venous (Phv) pressures during the double occlusion maneuver of simultaneous occlusions of the inflow and outflow perfusion lines. From the pressure gradients among Ppv, Ppo, Phvo, and Phv, the portal-hepatic venous resistance was assigned to three segments of the portal [Rpv = (Ppv − Ppo)/blood flow (Q)], sinusoidal [Rsinus = (Ppo − Phvo)/Q] and hepatic venous [Rhv = (Phvo − Phv)/Q] resistances. Rsinus, but not Rpv or Rhv, was significantly greater in BDL livers than in sham livers. Endothelin-1 (0.1–1 nM) increased Rpv and Rsinus to a similar magnitude, but not Rhv, in both sham and BDL. At 3 nM, the responsiveness of Rpv was smaller in BDL than in sham, but that of Rsinus were similar between in BDL and sham. In conclusion, increased sinusoidal resistance accounts for increased intrahepatic resistance of BDL-induced liver cirrhosis. Endothelin-1 contracts portal veins and sinusoids, but not hepatic veins, in both sham and cirrhotic livers. Sinusoidal contractility to endothelin-1 is not impaired in cirrhotic livers.     

Spectral analysing of portal vein Doppler signals in the cirrhosis patients

In this study, we have researched the efficacy of short-time Fourier transformation (STFT) of Doppler signals from the portal veins of healthy volunteers and cirrhosis patients. Sonogram and power spectral distribution for portal vein Doppler spectral waveform changes in the cirrhosis disease were utilized and these graphics compared with healthy volunteers. Five parameters were used to compare power spectrum graphics. Clear differences were detected in the calculated parameters between healthy and cirrhosis patients. It was seen that power spectral graphics and sonograms of portal vein Doppler signals may be used to determine cirrhosis disease.     

Prehepatic portal hypertension worsens the enterohepatic redox balance in thioacetamide-cirrhotic rats

Background: Oxidative stress has been reported as a key pathogenic factor in many human liver diseases and in experimental models of cirrhosis related to hepatotoxin administration. The aim of this study was to verify the hypothesis that prehepatic portal hypertension aggravates the enterohepatic redox imbalance in thioacetamide-cirrhotic rats. Materials and methods: Wistar male rats were used: Control (n = 9); rats with prehepatic portal hypertension by triple partial portal vein ligation (TPVL; n = 9); thioacetamide-cirrhotic rats (TAA; n = 9) and TPVL-rats associated to TAA administration (TPVL + TAA; n = 9). Three months after the operation, portal pressure (PP), mesenteric venous vasculopathy (MVV) and portosystemic collateral circulation were studied. Liver and ileal levels of malondialdehyde (MDA), as a lipid peroxidation marker, and catalase (CAT), glutathione peroxidase (GSH-Px), glutathione transferase (GSH-t) and cytosolic and mitochondrial superoxide dismutases (cSOD and mSOD), as antioxidative enzymatic mechanisms, were measured. Results: Liver and ileal MDA increased in all the experimental groups, although the higher increase occurred in the ileum of rats with portal hypertension. CAT levels decreased in the liver and the ileum in the three experimental groups. The decrease in liver and ileal GSH-Px and GSH-t was greater in rats with portal hypertension, alone or associated with TAA. mSOD activation was demonstrated in the liver when portal hypertension was added to TAA. On the contrary, this compensatory response was not activated in the ileum, where mSOD was significantly decreased. Conclusion: Prehepatic portal hypertension by triple partial portal vein ligation impaired the enterohepatic antioxidative activity and aggravated the intestinal oxidative stress in thioacetamide-cirrhotic rats.     

肝硬化肝门静脉血流超声测定与肝纤维化指标的比较

目的：探讨肝门静脉血流和肝纤维化指标对诊断肝硬化的诊断价值。方法：50例肝硬化患者和20例正常对照组用肝门静脉超声和放免法分别测定肝门静脉血流和肝纤维化指标。结果：肝硬化肝门静脉血流动力学指标均高于正常对照组（P〈0．05），并随着肝功能Child Puph分级程度严重而下降；活动性肝纤维化指标明显高于静止性肝硬化（P〈0．05～0．01）；超声与血清判断肝硬化的符合率比较大致相同。结论：肝门静脉超声和肝纤维化指标能判断肝硬化损害的程度。