Hypoxic hepatitis with marked elevation of serum ferritin probably due to activation of intrahepatic macrophages: another form of hypoxic hepatitis hitherto not reported?

BACKGROUND AND STUDY AIMS: Hypoxic hepatitis (HH) is an acute liver injury that develops in patients with underlying diseases, such as heart failure, respiratory failure, septic/toxic shock. However, some patients do not have underlying diseases or episodes which are known to result in HH. Here, we analyzed the clinical characteristics of this particular patient group (called 'unknown HH' hereafter) to understand its pathogenesis. PATIENTS AND METHODS: Between October 2010 and January 2016, 157 consecutive patients with acute liver injury were admitted to our hospital. Among these patients, 15 patients were categorized as unknown HH. Medical histories and blood test results of unknown HH were analyzed. RESULTS: Among 15 patients of unknown HH, 11 were habitual drinkers and all experienced one of digestive symptoms which might result in mild hypovolemia such as vomiting, diarrhea, appetite loss, and epigastralgia. All patients of unknown HH presented marked elevation of serum ferritin concentration paralleled with aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) concentrations. The serum levels of ferritin, ALT, LDH, and prothrombin time-international normalized ratio (PT-INR) were rapidly decreased during hospitalization and all 15 patients of unknown HH recovered without any complication. CONCLUSIONS: We found the particular group of HH with marked elevation of serum ferritin probably due to intrahepatic macrophage activation. Anti-inflammatory treatments might be effective for this group of hypoxic hepatitis.

Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease.

BACKGROUND & AIMS: In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD. METHODS: Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. RESULTS: TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. CONCLUSIONS: Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. LAY SUMMARY: Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.

Intraoperative Imaging Techniques to Visualize Hepatic (Micro)Perfusion: An Overview.

The microcirculation plays a crucial role in the distribution of perfusion to organs. Studies have shown that microcirculatory dysfunction is an independent predictor of morbidity and mortality. Hence, assessment of liver perfusion offers valuable information on the (patho)physiological state of the liver. The current review explores techniques in perfusion imaging that can be used intraoperatively. Available modalities include dynamic contrast-enhanced ultrasound, handheld vital microscopes, indocyanine green fluorescence angiography, and laser contrast speckle imaging. Dynamic contrast-enhanced ultrasound relays information on deep tissue perfusion and is a commonly used technique to assess tumor perfusion. Handheld vital microscopes provide direct visualization of the sinusoidal architectural structure of the liver, which is a unique feature of this technique. Intraoperative fluorescence imaging uses indocyanine green, a dye that is administered intravenously to visualize microvascular perfusion when excited using near-infrared light. Laser speckle contrast imaging produces non-contact large surface-based tissue perfusion imaging free from movement- or pressure-related artefacts. In this review, we discuss the intrinsic advantages and disadvantages of these techniques and their clinical and/or scientific applications.

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. SUMMARY: L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6-9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA's ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.

Short-term treatment with hepatoselective NO donor V-PYRRO/NO improves blood flow in hepatic microcirculation in liver steatosis in mice.

BACKGROUND: The impairment of liver sinusoidal endothelial cells (LSECs) function and diminished nitric oxide (NO) production has been regarded as an important pathogenic factor in liver steatosis. Restoring NO-dependent function was shown to counteract liver steatosis, obesity, and insulin resistance. However, it is not known whether restored liver perfusion and improvement in hepatic blood flow contributes to the anti-steatotic effects of NO. Taking advantage of in vivo MRI, we have examined the effects of short-term treatment with the hepatoselective NO donor V-PYRRO/NO on hepatic microcirculation in advanced liver steatosis. METHODS: Male C57BL/6 mice fed for six months a high fat diet (HFD; 60 kcal% of fat) were treated for 3 weeks with V-PYRRO/NO (twice a day 5mg/kg b.w. ip). An MRI assessment of liver perfusion using the FAIR-EPI method and a portal vein blood flow using the FLASH method were performed. Blood biochemistry, glucose tolerance tests, a histological evaluation of the liver, and liver NO concentrations were also examined. RESULTS: Short-term treatment with V-PYRRO/NO releasing NO selectively in the liver improved liver perfusion and portal vein blood flow. This effect was associated with a slight improvement in glucose tolerance but there was no effect on liver steatosis, body weight, white adipose tissue mass, plasma lipid profile, or aminotransferase activity. CONCLUSION: Short-term treatment with V-PYRRO/NO-derived NO improves perfusion in hepatic microcirculation and this effect may also contribute to the anti-steatotic effects of hepatoselective NO donors linked previously to the modulation of glucose and lipid metabolism in the liver.

Microcirculatory disturbances and cellular changes during progression of hepatic steatosis to liver tumors.

Non-alcoholic fatty liver disease is closely associated with metabolic syndrome and comprises a pathological spectrum of liver disease ranging from steatosis to steatohepatitis and can progress to fibrosis/cirrhosis and hepatocellular carcinoma. In 2013, a mouse model was described that mimics non-alcoholic fatty liver disease progression from steatohepatitis to tumors in a short time span and with high incidence. As microcirculatory disturbances play a crucial role in liver disease, the suitability of the steatosis-inflammation-tumor model for microcirculatory studies was assessed. Herein, we present a comprehensive view on morphological, microvascular, cellular, and functional aspects of non-alcoholic fatty liver disease progression in the steatosis-inflammation-tumor model using intravital microscopy, biochemical, and histological techniques. Mice develop steatohepatitis, mild fibrosis, and liver tumors at ages of 6, 12, and 20 weeks, respectively. Non-alcoholic fatty liver disease progression was accompanied by several general aspects of disease severity like increasing liver/body weight index, non-alcoholic fatty liver disease activity score, and hepatocellular apoptosis. Intravital microscopic analysis revealed significant changes in hepatic microcirculation with increasing structural alterations, elevated leukocyte adherence, and impaired nutritive perfusion. Non-alcoholic fatty liver disease was further characterized by a lower sinusoidal density with a striking rise at 20 weeks. The characteristic microcirculatory changes make the model a convenient tool for analysis of microcirculation during progression from steatosis to liver tumor. Impact statement Significant alterations of microcirculation contribute to progression of NAFLD, a chronic liver disease with increasing medical and socio-economic impact. Characterization of microcirculation in a NAFLD model reflecting all relevant stages of disease progression was still missing. Thus, we evaluated microcirculatory and cellular changes in a steatosis-inflammation-tumor model using in vivo microscopy. Analyses revealed increasing structural alterations, elevated leukocyte-endothelial interaction, and impaired nutritive perfusion. Thus, this model is suitable for further studies investigating therapeutic approaches targeting these progressive microcirculatory disturbances.

The therapeutic effects of cholecystokinin octapeptide on rat liver and kidney microcirculation disorder in endotoxic shock.

OBJECTIVES: Our previous studies demonstrated that pretreatment with cholecystokinin octapeptide (CCK-8) could alleviate endothelial cell injury and reverse abnormal vascular reactivity as well as reduce LPS-induced inflammation cascades, which suggested that CCK-8 plays a potential role in anti-endotoxic shock. The present study aimed to determine the therapeutic effects of CCK-8 on rat liver and kidney microcirculatory perfusion disorder under endotoxic shock (ES) conditions. MATERIALS AND METHODS: Sprague-Dawley rats were induced to lethal endotoxic shock by an injection of LPS. CCK-8 was administered 30 min after LPS injection. Either a specific CCK-1R antagonist or CCK-2R antagonist was injected before CCK-8 treatment. The mean arterial pressure (MAP), liver and kidney microcirculatory perfusion, and heart rate (HR) were recorded with a multi-channel data acquisition system. The serum concentrations of alanine aminotransferase (ALT) and creatinine (Cr) were measured, and the histopathological changes in the liver and kidney were also observed. RESULTS: Administration of CCK-8 significantly delayed the LPS-induced decreases in not only the liver and kidney microcirculation perfusion but also the HR. The pathology changes induced by LPS in the liver and kidney tissues were significantly mitigated in the LPS + CCK-8 group. The levels of ALT and Cr in the serum of the LPS + CCK-8 group were obviously lower than those in the LPS group. In addition, the specific antagonist at the CCK-2 receptor (CCK-2R) abrogated the action of CCK-8 significantly. CONCLUSIONS: These results indicated that CCK-8 has potential therapeutic effects on microcirculation failure in an ES rat model via the CCK-2 receptor.

Alteration of intrahepatic microcirculation in cirrhotic livers.

From a hemodynamic point of view, hepatic vascular resistance and portal inflow determine the level of portal pressure. Factors that determine hepatic vascular resistance include both structural and dynamic components. Among the structural components are histological characteristics such as steatosis, fibrosis, regeneration nodules, and neo-angiogenesis. Dynamic structures include cells with contractile properties such as hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, and Kupffer cells. The contributions of the interactions between four cells in cirrhotic livers resulted in hepatic endothelial dysfunction, hepatic microcirculatory dysfunction, hepatic venous dysregulation, hepatic fibrogenesis, and subsequently increased intrahepatic resistance and portal hypertension in cirrhosis. The pathogenic mechanisms that trigger the associated abnormalities in hepatic microcirculations include persistent endotoxemia, increased hepatic oxidative stress, activated endocannabinoids substances, pathogenic sinusoidal remodeling, and hypoperfusion in cirrhotic livers. Cumulative data suggested that various therapeutic strategies targeting hepatic microcirculation provided effective improvement of the systemic abnormalities of cirrhosis. Accordingly, the mechanistic and therapeutic approaches focusing on the disarrangement of hepatic microcirculation will be introduced in this article.

Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice.

BACKGROUND & AIMS: Bile formation and secretion are essential functions of the hepatobiliary system. Bile flow is generated by transepithelial transport of water and ionic/nonionic solutes via transcellular and paracellular pathways that is mainly driven by osmotic pressure. We examined the role of tight junction-based paracellular transport in bile secretion. Claudins are cell-cell adhesion molecules in tight junctions that create the paracellular barrier. The claudin family has 27 reported members, some of which have paracellular ion- and/or water-channel-like functions. Claudin 2 is a paracellular channel-forming protein that is highly expressed in hepatocytes and cholangiocytes; we examined the hepatobiliary system of claudin 2 knockout (Cldn2(-/-)) mice. METHODS: We collected liver and biliary tissues from Cldn2(-/-) and Cldn2(+/+) mice and performed histologic, biochemical, and electrophysiologic analyses. We measured osmotic movement of water and/or ions in Cldn2(-/-) and Cldn2(+/+) hepatocytes and bile ducts. Mice were placed on lithogenic diets for 4 weeks and development of gallstone disease was assessed. RESULTS: The rate of bile flow in Cldn2(-/-) mice was half that of Cldn2(+/+) mice, resulting in significantly more concentrated bile in livers of Cldn2(-/-) mice. Consistent with these findings, osmotic gradient-driven water flow was significantly reduced in hepatocyte bile canaliculi and bile ducts isolated from Cldn2(-/-) mice, compared with Cldn2(+/+) mice. After 4 weeks on lithogenic diets, all Cldn2(-/-) mice developed macroscopically visible gallstones; the main component of the gallstones was cholesterol (>98%). In contrast, none of the Cldn2(+/+) mice placed on lithogenic diets developed gallstones. CONCLUSIONS: Based on studies of Cldn2(-/-) mice, claudin 2 regulates paracellular ion and water flow required for proper regulation of bile composition and flow. Dysregulation of this process increases susceptibility to cholesterol gallstone disease in mice.

Laser speckle contrast imaging for assessment of abdominal visceral microcirculation in acute peritonitis: does sequential impairments exist?

OBJECTIVE: It is believed that the microcirculation of multiple organs is impaired during acute peritonitis, however whether distinct susceptibilities of visceral microvasculature exist is still unknown. The present study aims to verify whether the microcirculatory alterations occur sequentially among multiple abdominal viscera during acute peritonitis. MATERIALS AND METHODS: Acute peritonitis was achieved on 29 Sprague-Dawley rats through colon ascendens stent peritonitis (CASP) model. With laser speckle contrast imaging (LSCI), the microcirculation of the liver, ileum and renal cortex was monitored in each rat at baseline before CASP sepsis and continued monitoring at 4h, 8h, or 12h after the surgery. Another 9 rats served for sham operation. One-way analysis of variance with a post hoc Dunnett's test was used for analysis. RESULTS: The ileum microcirculation was impaired earliest from 342.1±61.0 laser speckle perfusion unit (LSPU) at baseline to 271.7±74.0 LSPU at 4h (P<0.05), while the decline of renal microcirculation was not obvious until 8h after peritonitis (289.1±111.2 vs 376.2±53.4, P<0.05). However hepatic microcirculation was not significantly changed during 12h of observation period. CONCLUSION: The microcirculation of various viscera has shown distinct susceptibilities to acute peritonitis: the ileum is more susceptible than the kidney, while the hepatic microcirculation seems to be the most resistant to peritonitis.

Microcirculation changes during liver resection--a clinical study.

BACKGROUND: In this study we aimed to evaluate effects of liver resection on hepatic microcirculation. In addition we wanted to study if histological liver damage could be detected intra-operatively. PATIENTS AND METHODS: 40 patients undergoing hepatic resection were included and grouped according to if they were operated with a major or minor resection. Hepatic microcirculation measurements were made intra-operatively before and after liver resection with sidestream dark-field (SDF) imaging. Red blood cell velocity (RBCV), sinusoidal diameter and functional sinusoidal density were determined. RESULTS: After hepatic resection RBCV increased in both the minor and major groups (44 µm/s, P=0.016 and 121 µm/s, P=0.002). RBCV in patients with histological damages was 225 (148-464) µm/s vs. 161 (118-329) µm/s in patients with no damage (P=0.016). CONCLUSION: A hepatic resection leads to an increase of sinusoidal RBCV. SDF imaging could potentially be used to intraoperatively identify histological damages.

A 3D porous media liver lobule model: the importance of vascular septa and anisotropic permeability for homogeneous perfusion.

The hepatic blood circulation is complex, particularly at the microcirculatory level. Previously, 2D liver lobule models using porous media and a 3D model using real sinusoidal geometries have been developed. We extended these models to investigate the role of vascular septa (VS) and anisotropic permeability. The lobule was modelled as a hexagonal prism (with or without VS) and the tissue was treated as a porous medium (isotropic or anisotropic permeability). Models were solved using computational fluid dynamics. VS inclusion resulted in more spatially homogeneous perfusion. Anisotropic permeability resulted in a larger axial velocity component than isotropic permeability. A parameter study revealed that results are most sensitive to the lobule size and radial pressure drop. Our model provides insight into hepatic microhaemodynamics, and suggests that inclusion of VS in the model leads to perfusion patterns that are likely to reflect physiological reality. The model has potential for applications to unphysiological and pathological conditions.

Preventing intra-abdominal adhesions with a sodium hyaluronate carboxymethylcellulose membrane enabled visualization of hepatic microcirculation.

We aimed to evaluate whether using sodium hyaluronate carboxymethylcellulose membrane (Seprafilm™) can facilitate assessment of hepatic microcirculation via orthogonal polarization spectroscopy (OPS) by preventing intra-abdominal adhesions and whether Seprafilm™ as a foreign material can evoke local or systemic inflammatory reactions. After the right median hepatic vein was ligated, rats received either placement of Seprafilm™ or untreated with observation of 1 or 4 weeks (n = 6/group). Hepatic microcirculation was visualized. Systemic and local inflammatory reactions were evaluated by blood count, histology and immunohistochemical staining for CD68. Seprafilm™ significantly (P < 0.05) prevented intra-abdominal adhesion formation compared to non-Seprafilm™ groups (adhesion score: 0 vs 1.3 ± 0.5 at POW1 and 0.3 ± 0.5 vs 3.5 ± 1.4 at POW4). Placement of Seprafilm™ provided sufficient liver surface for acquisition of OPS videos during the harvest procedure. Adhesiolysis in non-Seprafilm™ groups prevented visualization of hepatic microcirculation. A severe local foreign body reaction with formation of a "fibrin-like" membrane containing CD68-positive inflammatory histiocytic cells and mesothelial cells was observed in Seprafilm™ groups even at POW4. Use of Seprafilm™ conferred visualization of hepatic microcirculation after long term observation in experimental setting. In clinical situation, we would suggest being very cautious in immuno-compromised patients because of an ongoing local foreign body reaction caused by Seprafilm™.

The role of ß2-integrins and CD44 in intrahepatic leukocyte sequestration.

BACKGROUND: Intrahepatic leukocyte sequestration is a component of the systemic inflammatory response, and can be triggered by systemic immune dysfunction during sepsis. METHODS: To examine leukocyte sequestration over time during endotoxemia, its influence on liver function, and the role of specific cell adhesion molecules, endotoxemia was induced in mice by intraperitoneal application of lipopolysaccharides. Leukocyte sequestration was measured at different times after induction using fluorescence microscopy. Liver injury was evaluated by measuring liver enzymes and tissue histology. RESULTS: Endotoxin induces a strong leukocyte sequestration in the liver microvasculature. This was associated with an induction of liver injury, as reflected by an increase in enzyme levels and histomorphologic changes. Intrahepatic leukocyte sequestration was reduced in CD44(-/-), but not in intercellular adhesion molecule-1 (ICAM-1)(-/-), lymphocyte function-associated antigen-1(-/-), and macrophage-1(-/-) antigen mice. Leukocyte sequestration dropped in ICAM-1(-/-), lymphocyte function-associated antigen-1(-/-), and macrophage-1(-/-) mice in later stages, but remained stable in wild-type and CD44(-/-) animals. Reduced leukocyte sequestration in CD44(-/-) mice was accompanied by a significant decrease in transferase levels. CONCLUSIONS: Endotoxemia induces stable intra-sinusoidal leukocyte sequestration, which contributes to liver injury. At the initial stage of the endotoxemia, leukocyte sequestration depends on CD44 but is independent of ICAM-1 and ß2-integrins. Intercellular adhesion molecule-1 and ß2-integrins, but not CD44, stabilize leukocyte sequestration during the later stage of endotoxemia. The molecular modulation of intrahepatic leukocyte sequestration may have important therapeutic implications in sepsis, reducing liver injury, and improving immune defense capabilities.

Contrast-enhanced ultrasound evaluation of hepatic microvascular changes in liver diseases.

AIM: To assess if software assisted-contrast-enhanced ultrasonography (CEUS) provides reproducible perfusion parameters of hepatic parenchyma in patients affected by chronic liver disease. METHODS: Forty patients with chronic viral liver disease, with (n = 20) or without (n = 20) cirrhosis, and 10 healthy subjects underwent CEUS and video recordings of each examination were then analysed with Esaote's Qontrast software. CEUS dedicated software Qontrast was used to determine peak (the maximum signal intensity), time to peak (TTP), region of blood value (RBV) proportional to the area under the time-intensity curve, mean transit time (MTT) measured in seconds and region of blood flow (RBF). RESULTS: Qontrast-assisted CEUS parameters displayed high inter-observer reproducibility (κ coefficients of 0.87 for MTT and 0.90 TTP). When the region of interest included a main hepatic vein, Qontrast-calculated TTP was significantly shorter in cirrhotic patients (vs non-cirrhotics and healthy subjects) (71.0 ± 11.3 s vs. 82.4 ± 15.6 s, 86.3 ± 20.3 s, P < 0.05). MTTs in the patients with liver cirrhosis were significantly shorter than those of controls (111.9 ± 22.0 s vs. 139.4 ± 39.8 s, P < 0.05), but there was no significant difference between the cirrhotic and non-cirrhotic groups (111.9 ± 22.0 s vs. 110.3 ± 14.6 s). Peak enhancement in the patients with liver cirrhosis was also higher than that observed in controls (23.9 ± 5.9 vs. 18.9 ± 7.1, P = 0.05). There were no significant intergroup differences in the RBVs and RBFs. CONCLUSION: Qontrast-assisted CEUS revealed reproducible differences in liver perfusion parameters during the development of hepatic fibrogenesis.

Liver anatomy: microcirculation of the liver.

Comprehension of the structural and functional characteristics of the hepatic microcirculation can help improve the design, planning, and practice of imaging-guided treatment for hepatic tumors and for portal vein embolization (PVE). The hepatic microcirculation derives dual blood supply from the portal vein and the hepatic artery. The terminal portal venules directly connect to the hepatic sinusoids, but the terminal hepatic arterioles connect to arterioportal communications before entering the sinusoids: the peribiliary plexus, the terminal arteriosinus twigs, the vasa vasorum on the portal vein, and the direct arterioportal anastomosis. These communications play important roles in the balance of blood perfusion to the liver parenchyma and in controlling the blood supply to hepatic tumors and the anticipated remnant liver (in cases of PVE). At the microcirculatory level, various embolic agents present different distribution patterns. To further our understanding, iodized oil has been found to pass into the portal vein after hepatic arterial administration through the peribiliary plexus and subsequently traverses the sinusoids to enter the lungs and then the systemic circulation. Ultimately, a thorough knowledge of the host environment at the microcirculatory level is essential in developing strategies for both tumor treatment and for inducing liver regeneration.

Ginkgo Biloba Extract EGb 761 Alleviates Hepatic Fibrosis and Sinusoidal Microcirculation Disturbance in Patients with Chronic Hepatitis B.

BACKGROUND: Few clinical data are available regarding the effect of Ginkgo biloba extract (EGb 761) on liver microcirculation and fibrosis. This randomized, controlled trial is to investigate the effect of Ginko biloba extract EGb 761 on liver fibrosis and hepatic microcirculation in patients with chronic hepatitis B. METHODS: Sixty-four patients with chronic hepatitis B were randomized for intention-to-treat. Thirty-two patients were assigned to treated group receiving EGb 761 plus polyunsaturated phosphatidylcholine (Essentiale), 32 patients received Essentiale as controls. Blood samples were taken for measurement of transforming growth factor beta-1 (TGF-ß1), platelet activate factor (PAF), endothelin 1 (ET-1). Twenty-six patients in treated group and 21 patients in control group underwent liver biopsies for histology before and after treatment. Ultrastructural study for sinusoidal microcirculation before and after treatment was carried out on 10 randomly selected patients in each group. RESULTS: In the treated group, after EGb 761 treatment, there was a significant reduction of blood TGF- ß1, PAF and ET-1 (p<0.05), whereas this was not observed in the controls. After treatment in both groups, there were significant decrease of ALT, TBil and PT (p<0.05), and significant increase of ALB (p<0.05). Hepatic inflammation and fibrosis significantly alleviated in the treated group, but not in the controls. After EGb 761 treatment, electron microscopy showed red blood cell aggregates and microthrombosis disappeared or decreased in sinusoids; collagen deposits in sinusoidal lumen and Disse space reduced; sinusoidal capillarization alleviated. CONCLUSIONS: EGb 761 can improve sinusoidal microcirculation, alleviate inflammation and inhibit fibrosis through multiple mechanisms, it is effective in the treatment of chronic liver diseases.