肝硬化患者胃黏膜ghrelin表达及其临床意义

研究肝硬化患者胃黏膜ghrelin表达及其意义.选择肝硬化患者36例和内镜下胃黏膜大致正常者15例为对照组,测定肱三头肌皮褶厚度(triceps skinfold thickness,TSF)、血糖、胰岛素,进行食欲评价.肝硬化组胃黏膜表达ghrelin阳性细胞面积显著高于对照组(P＜0.001),且随着Child-Pugh分级增高有递增趋势.肝硬化组空腹血糖、胰岛素均显著高于对照组(P＜0.001,P＜0.05);胰岛素敏感指数(insulin sensitivity index,ISI)显著低于对照组(P＜0.05).肝硬化组ghrelin阳性细胞面积与食欲(r=-0.432)、TSF(r=-0.525)、ISI(r=-0.509)呈负相关(P＜0.05),与血糖(r=0.449)呈正相关(P＜0.05).肝硬化时ghrelin表达增高是机体对能量负平衡状态的一种适应性反应.胃黏膜ghrelin高表达可能参与了肝硬化患者的胰岛素抵抗作用.     

Uncoupling of sympathetic nervous system and hypothalamic-pituitary-adrenal axis in cirrhosis

Background and Aim: The hypothalamic‐autonomic nervous system (HANS) axis and the hypothalamic‐pituitary‐adrenal (HPA) axis are stimulated in parallel in response to stress factors under healthy conditions. This physiological synergism of the axes aims at optimizing anti‐inflammatory actions. Therefore, we investigated whether this synergism is altered in patients with liver cirrhosis. Methods: As a typical marker of the HANS axis neuropeptide Y (NPY is a neurotransmitter of the sympathetic nerve terminal) and of the HPA axis, cortisol together with adrenocorticotropic hormone (ACTH) and cortisol‐binding globulin (CBG), were measured in samples from control subjects and patients with liver cirrhosis. Results: Plasma NPY was found to be increased in cirrhotic patients compared to control subjects (P < 0.01). This increase was observed to be independent of the severity of liver disease (Child class). Serum cortisol was decreased in cirrhotics, particularly in patients with Child A cirrhosis. Plasma NPY was positively correlated with serum cortisol in control subjects (r = 0.32, P < 0.05) reflecting the parallel activation of both axes under the normal condition. However, serum cortisol was not correlated with plasma NPY in cirrhotic patients. For the subgroup of Child A patients, even a negative correlation between NPY and cortisol was observed (r = ?0.43, P < 0.05). No significant change in serum levels of ACTH and its positive correlation with serum cortisol was observed in cirrhotic patients. Conclusions: The present study demonstrates that the two stress axes seem to act in parallel fashion in control subjects but are uncoupled in liver cirrhosis. We discuss how uncoupling of the two anti‐inflammatory axes can occur and may contribute to the increased susceptibility for infections and lethal complications in cirrhotic patients.     

Carbohydrate and lipid metabolism in cirrhosis. Evidence that hepatic uptake of gluconeogenic precursors and of free fatty acids depends on effective hepatic flow

Splanchnic arteriovenous differences for several intermediary metabolites of carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in seven normal subjects, eight patients with cirrhosis, and six patients with cirrhosis after surgical portosystemic shunt ( SPSS ) after an overnight fast. Arteriovenous differences in the legs were also determined together with flux measurement. The individual turnover rates of acetoacetate (AcAc) and 3 hydroxybutyrate (beta OHB) were also determined by means of isotopic techniques. Splanchnic gluconeogenic precursors and FFA uptakes were lower in cirrhotic patients with SPSS than in normal subjects (P less than 0.05 and P less than 0.01, respectively). Splanchnic triglyceride output was also lower in cirrhotic patients with SPSS than in normal subjects (P less than 0.01), whereas no significant differences were found for AcAc, beta OHB, and glucose release. In the group of cirrhotic patients without SPSS , those patients with negligible signs of portal systemic shunt and normal splanchnic blood flow had uptake of gluconeogenic precursors and of FFA normal or higher than that of normal subjects, whereas those patients with signs of spontaneous portal systemic shunt behaved like cirrhotic patients with SPSS . Alanine release from the leg was lower in both cirrhotic patient groups. Tracer determined hepatic output of AcAc and beta OHB was higher in cirrhotic patients with SPSS (P less than 0.05). Plasma clearance rates of AcAc and beta OHB were significantly elevated in both cirrhotic patient groups. Close agreement was found between tracer and catheterization techniques in the evaluation of ketone body production in cirrhotic patients with SPSS , whereas in cirrhotic patients without SPSS tracer determined hepatic output was slightly lower, possibly because of extrahepatic splanchnic tissue ketone body uptake. In conclusion, our data in patients with cirrhosis indicate that: 1) splanchnic uptake of gluconeogenic precursors and of FFA was related to the degree of portal systemic shunt, e.g. to the degree of effective hepatic blood flow; 2) liver triglyceride but not ketone body output was decreased by the impaired FFA (and glycerol) liver uptake; 3) the higher circulating levels of gluconeogenic precursors (except alanine) and of FFA appeared at least partially due to lower hepatic removal of these metabolites; and 4) peripheral use of ketone bodies was increased and alanine release from the leg reduced in patients with cirrhosis.     

Expression of growth hormone receptor and its mRNA in hepatic cirrhosis

AIM: To investigate the expression of growth hormone receptor (GHR) and mRNA of GHR in cirrhotic livers of rats with the intension to find the basis for application of recombinant human growth hormone (rhGH) to patients with liver cirrhosis.METHODS: Hepatic cirrhosis was induced in SpragueDawley rats by administration of thioacetamide intraperitoneally for 9-12 weeks. Collagenase Ⅳ was perfused in situ for isolation of hepatocytes. The expression of GHR and its mRNA in cirrhotic livers was studied with radio-ligand binding assay, RT-PCR and digital image analysis.RESULTS: One class of specific growth hormone-binding site, GHR, was detected in hepatocytes and hepatic tissue of cirrhotic livers. The binding capacity of GHR (RT, fmol/mg protein) in rat cirrhotic liver tissue (30.8±1.9) was significantly lower than that in normal control (74.9±3.9) at the time point of the ninth week after initiation of induction of cirrhosis (n=10, P＜0.05), and it decreased gradually along with the accumulation of collagen in the process of formation and development of liver cirrhosis (P＜0.05). The number of binding sites (×10 4/cell) of GHR on rat cirrhotic hepatocytes (0.86±0.16) was significantly lower than that (1.28±0.24)in control (n= 10, P＜0.05). The binding affinity of GHR among liver tissue, hepatocytes of various groups had no significant difference (P＞0.05). The expression of GHR mRNA (riOD,pixel) in rat cirrhotic hepatic tissues (23.3±3.1) was also significantly lower than that (29.3±3.4) in normal control (n=10, P＜0.05).CONCLUSION: The growth hormone receptor was expressed in a reduced level in liver tissue of cirrhotic rats,and lesser expression of growth hormone receptors was found in a later stage of cirrhosis. The reduced expression of growth hormone receptor was partly due to its decreased expression on cirrhotic hepatocytes and the reduced expression of its mRNA in cirrhotic liver tissue.     

The Role of Nitric Oxide in the Expression of Renal Aquaporin 2 in a Cirrhotic Rat Model: Does an AVP-Independent Mechanism Exist for the Regulation of AQP2 Expression?

The aquaporin (AQP) water channel is expected to play a decisive role of hyponatremia and water retention in cirrhotic patients. Despite the importance of the water channel, however, previous findings vary widely when it concerns AQP2 of the kidneys in subjects with cirrhosis. The purpose of this study was to investigate the expression of AQP2 in the distal renal tubule in cirrhosis, and the presence of the nitric oxide-AQP2 signaling pathway as a possible vasopressin-aquaporin-independent pathway. Sixty male Wister rats were assigned to six groups: (1) control; (2) TAA (thioacetamide); (3) TAA with nitric oxide donor; (4) TAA with nitric oxide inhibitor; (5) TAA with HMG CoA reductase inhibitor; (6) TAA with tetrahydrobiopterin. Immunohistochemical staining for AQP2, real-time polymerase chain reaction (PCR) for AQP2 and 3, citrulline assay, and renal cGMP concentration were measured. The AQP2-positivity of cirrhotic rats were higher than the controls (P < 0.05). The AQP2-positivity decreased in the nitric oxide donor group, but the proportion rose back up when the subjects were injected with the nitric oxide inhibitor (P < 0.05). The expression of AQP2 and AQP3 mRNA was also found to show an increase in the cirrhotic group as compared with the normal controls (P < 0.05). The cirrhotic group administered with nitric oxide donor showed a significant decline in the expression of the mRNA. The control group’s cGMP concentration was lower than that of the cirrhotic group (P < 0.05), but a comparison of the two groups injected with nitric oxide modulators, such as statin and BH4, did not show significant differences in the cGMP concentration level. The expression of AQP2 of the kidneys increased in the cirrhotic rats. AQP2 had relations to the activity changes of nitric oxide synthetase.     

Role of chronic Helicobacter pylori infection in hyperdynamic circulation of cirrhotic patients

BACKGROUND/AIMS: Hyperdynamic circulation observed in portal hypertension is characterized by generalized vasodilatation, increased cardiac index, and increased systemic and regional blood flows, and mediated at least partly by increased nitric oxide activities. Recent studies have demonstrated that Helicobacter pylori (H. pylori) infection can stimulate nitric oxide synthase expression and activities. This study investigated if chronic H. pylori infection might be involved in the development of hyperdynamic circulation in cirrhotic patients. METHODOLOGY: Fifty-eight patients with cirrhosis and thirty-six healthy subjects entered this study. The serologic evidence of H. pylori infection was determined with ELISA in both groups. In addition, in cirrhotic patients hemodynamic studies were performed by Swan-Ganz catheterization and thermodilution technique. RESULTS: No significant differences in age (65.5 +/- 0.8 vs. 63.7 +/- 1.1 years), sex (male/female: 43/15 vs. 29/7) and seroprevalence of H. pylori (74.1% vs. 80.6%) were observed between cirrhotic patients and healthy subjects (P > 0.05). The seropositive rate of H. pylori in patients with cirrhosis was not associated with severity of cirrhosis and size of esophageal varices (P > 0.05). There were no significant differences in systemic vascular resistance and hepatic venous pressure gradient between cirrhotic patients with and those without chronic H. pylori infection (P > 0.05). CONCLUSIONS: The seroprevalence of H. pylori in cirrhotic patients is similar to that of healthy controls, and not related to the severity of cirrhosis and degree of portal hypertension. Chronic H. pylori infection does not play a major role in the hyperdynamic circulation observed in cirrhotic patients.     

Delayed gastric emptying in patients with liver cirrhosis

Using a scintigraphic technique, we investigated gastric emptying of a semisolid meal in 20 patients with liver cirrhosis and in 10 control subjects and correlated gastric emptying with gastrointestinal symptoms and with autonomic nervous function as determined by R-R interval variation on the electrocardiogram. All subjects lacked endoscopic abnormalities that might explain their gastrointestinal symptoms. None had alcoholic liver disease, diabetes, or other diseases known to affect gastric emptying. The half-time for gastric emptying was significantly prolonged in the cirrhotic patients (51.3±16.6 minutes) as compared with control subjects (29.9±8.4) (P<0.01). There was a significant correlation between the gastrointestinal symptom score and the half-time for gastric emptying (r=0.46,P<0.05) in the cirrhotic patients. However, the decreases in R-R interval variation and gastric emptying were not significantly correlated. These observations indicate that delayed gastric emptying is frequently present in patients with liver cirrhosis and may produce their gastrointestinal symptoms.     

Reduced hepatic glycogen stores in patients with liver cirrhosis

Abstract: Background: Patients with alcoholic liver cirrhosis have reduced hepatic glycogen stores but the mechanisms leading to this finding are not clear. Methods: We therefore determined the hepatic glycogen content in patients with alcoholic (n = 9) or biliary cirrhosis (n = 8), and in control patients undergoing liver surgery (n = 14). All patients were in the postabsorptive state. In addition, we performed a morphometric analysis of the livers, and measured activities and mRNA expression of several enzymes involved in glycogen metabolism. Cirrhotic and control patients were similar regarding age and body weight. Results: Cirrhotic patients had a reduced glycogen content per gram liver wet weight (17 ± 11 versus 45 ± 17 mg/g, P < 0.05), per milliliter hepatocytes (28 ± 16 versus 52 ± 21 mg/ml, P < 0.05) and per liver (28 ± 17 versus 64 ± 22 g, P < 0.05), the reduction being observed in both patients with alcoholic or biliary cirrhosis. Liver histology confirmed these findings and revealed that the decrease in liver glycogen in cirrhotic patients was not homogenous across cirrhotic lobules. Activities of glycogen synthase and phosphorylase (total activity and active form) were not different between cirrhotic and control patients, whereas hepatic mRNA expression was decreased in cirrhotics by approximately 50%. The activity of glucokinase was decreased in cirrhotic as compared in control patients (0.06 ± 0.30 versus 0.42 ± 0.21 U/ml hepatocytes, P < 0.05), the reduction being observed in both patients with alcoholic or biliary cirrhosis. Conclusions: We conclude that patients with alcoholic or biliary cirrhosis have decreased hepatic glycogen stores per volume of hepatocytes and per liver. Decreased activity of glucokinase may represent an important mechanism leading to this finding.     

The relationship between insulin sensitivity and skeletal muscle enzyme activities in hepatic cirrhosis

We have examined the hypothesis that insulin insensitivity in hepatic cirrhosis is related to abnormalities of glycogen deposition and skeletal muscle enzyme activities. Otherwise well patients with biopsy-proven hepatic cirrhosis secondary to previous excess alcohol intake were studied. Prior to study, in basal state, patients had identical blood glucose concentrations but raised serum insulin concentrations (cirrhotic: 8.5 +/- 0.8 mU per liter; matched control subjects: 5.7 +/- 0.5 mU per liter, p less than 0.01). Muscle glycogen content, glycogen synthase activity and pyruvate dehydrogenase activity were normal in the basal state. The cirrhotic patients required less glucose to maintain the clamp in response to 0.1 unit per kg per hr insulin (6.7 +/- 0.5 vs. control 8.3 +/- 0.4 mg per kg per min, p less than 0.05) and deposited less glycogen in muscle during the clamp (8.6 +/- 0.5 vs. 12.0 +/- 1.4 mg per gm protein, p less than 0.05). Glycogen deposition correlated with clamp glucose requirement in the cirrhotic patients (r = 0.78, p less than 0.05). The expressed activity of glycogen synthase activity was significantly lower in cirrhotic patients at the end of the clamp (26.5 +/- 1.1% vs. 30.9 +/- 1.6%) and again correlated with clamp glucose requirement (r = 0.82, p less than 0.05). Skeletal muscle pyruvate dehydrogenase activity was not different in patients and control subjects. Insulin insensitivity in hepatic cirrhosis appears to be related to abnormalities of glucose deposition as glycogen in skeletal muscle.     

Changes in brain catecholamine levels in human cirrhotic hepatic encephalopathy

Hepatic encephalopathy (HE) is currently felt to be secondary to a disturbance in the metabolism of cerebral catecholamines with a decline in dopamine and noradrenaline and a rise in the false neurotransmitter octopamine. The aim of this study was to evaluate brain tissue levels of dopamine, noradrenaline, and octopamine in patients with cirrhosis and HE. This study includes 34 patients: 22 were cirrhotic, 12 were control subjects. Among the 22 cirrhotic patients, 19 had HE, three did not. Tissue specimens were obtained at necropsy from the locus niger, caudate nucleus, hypothalamus, thalamus and frontal cortex, and from the frontal cortex during neurosurgical procedures. Our results showed that (1) dopamine and noradrenaline levels are identical in cirrhotic patients with or without HE and in patients without liver disease (P < 0.05); (2) octopamine levels are higher in control subjects than in patients with cirrhosis and HE. In conclusion, there is no decline in dopamine and noradrenaline levels in the brain tissues of cirrhotic patients with HE, and this is in contradication with the animal findings; octopamine levels are not raised. Hepatic encephalopathy in human liver cirrhosis does not seem to be secondary to a disturbance in cerebral catecholamines.     

Incidence of toxoplasmosis in patients with cirrhosis

AIM: It is known that toxoplasmosis rarely leads to various liver pathologies, most common of which is granulomatose hepatitis in patients having normal immune systems. Patients who have cirrhosis of the liver are subject to a variety of cellular as well as humoral immunity disorders. Therefore, it may be considered that toxoplasmosis can cause more frequent and more severe diseases in patients with cirrhosis and is capable of changing the course of the disease. The aim of this study was to investigate the frequency of toxoplasmosis in patients with cirrhosis. METHODS: Serum samples were taken from 108 patients with cirrhosis under observation in the Hepatology Polyclinic of the Gastroenterology Clinic, and a control group made up of 50 healthy blood donors. IFAT and ELISA methods were used to investigate the IgG and IgM antibodies, which had developed from these sera. RESULTS: Toxoplasma IgG and IgM antibody positivity was found in 74 (68.5%) of the 108 cirrhotic patients and 24 (48%) of the 50 people in the control group. The difference between them was significant (P<0.05). CONCLUSION: In conclusion, it was found that the toxoplasma sero-prevalence in the cirrhotic patients in this study was higher. Cirrhotic patients are likely to form a toxoplasma risk group. More detailed studies are needed on this subject.     

Plasma interleukin-8 levels in patients with post-hepatitic cirrhosis: Relationship to severity of liver disease, portal hypertension and hyperdynamic circulation

The present study investigated plasma levels of interleukin-8 (IL-8) in patients with post-hepatitic cirrhosis and correlated it with the severity of liver diseases and haemodynamic parameters. Plasma IL-8 levels were significantly higher in 57 post-hepatitic cirrhotic patients (7.5 ± 1.8 pg/mL; P< 0.005) than those in 41 healthy subjects (2.0 ± 0.2 pg/mL). Elevated (> 5 pg/mL) plasma IL-8 levels were found in up to 30% of cirrhotic patients. In cirrhotic patients, plasma IL-8 levels progressively increased in relation to the severity of liver dysfunction (4.5 ± 1.0, 4.9 ± 1.4 and 20.5 ± 8.3 pg/mL for Pugh's class A, B and C, respectively; P<0.005). A significant correlation was observed between plasma IL-8 levels and serum bilirubin levels (r = 0.72; P<0.001). There were no differences in the hepatic venous pressure gradient (15.4 ± 1.1 vs 15.1 ± 0.9 mmHg; P>0.05) and systemic vascular resistance (1119 ± 118 vs 1199 ± 54 dyn.s/cm⁵; P>0.05) between cirrhotic patients with and without elevated plasma IL-8 levels. In addition, plasma IL-8 levels did not correlate with hepatic venous pressure gradient (r = 0.26; P>0.05) and systemic vascular resistance (r=-0.24; P>0.05). These results demonstrate that plasma IL-8 levels are increased in patients with post-hepatitic cirrhosis. The severity of liver cirrhosis is an important factor for the occurrence of enhanced IL-8 levels. IL-8 does not play a role in the hyperdynamic circulation observed in patients with post-hepatitic cirrhosis.     

Insulin,C-peptide and glucagon levels during ogtt in hepatic cirrhosis and in patients with prehepatic block

Summary In order to investigate pancreatic B-cell function in hepatic cirrhosis and to elucidate the role of porto-caval shunt-circulation in the development of hyperinsulinism and hyperglucagonemia in cirrhotic patients, blood glucose, plasma insulin and glucagon, and serum C-peptide concentrations were measured during OGTT in 11 control and 16 cirrhotic subjects as well as in 7 patients with prehepatic block secondary to thrombosis of the portal vein. Insulin and glucagon levels were significantly higher in the cirrhotic than in the control group (for insulin: p<0.01, <0.001, <0.01 and <0.05 at 0, 60, 90 and 120 min, respectively; for glucagon: p<0.01, <0.01, and <0.05 at 0, 30 and 60 min, respectively). Serum C-peptide levels were, however, similar in the two groups with the exception of the 30-min value, which was significantly lower in the cirrhotic group (p<0.05). Plasma insulin and glucagon concentrations in patients with prehepatic block were similar to those of the controls but significantly lower than the values found in cirrhotic patients (for insulin: p<0.05 and <0.01 at 30 and 60 min, respectively; for glucagon: p<0.01, <0.01 and <0.05 at 0, 30, 60 min, respectively). Serum C-peptide levels of these patients were not significantly different either from the control values or from those obtained in the cirrhotic group. Accordingly, pancreatic B-cell secretion is not increased in hepatic cirrhosis. Hence, the hyperinsulinism is due to decreased hepatic degradation of the hormone. Decreased degradation of both insulin and glucagon should be attributed mainly to parenchymal liver damage, rather than porto-systemic shunting.     

EUS in cirrhotic patients with and without prior variceal hemorrhage in comparison with noncirrhotic control subjects

BACKGROUND: Endoscopic ultrasound (EUS) was used to evaluate cirrhotic patients with and without prior variceal hemorrhage. The findings were compared with those of EUS in noncirrhotic control subjects to determine EUS features indicative of cirrhosis and of a risk for variceal hemorrhage. METHODS: Patients with cirrhosis undergoing indicated endoscopic screening for varices or surveillance after endoscopic therapy for variceal hemorrhage were studied and compared with healthy noncirrhotic control patients undergoing EUS for benign conditions. RESULTS: Sixty-six cirrhotic patients (31 with prior hemorrhage) and 32 control patients were studied. Nonhemorrhage cirrhotic patients had more severe liver disease by Child's class (p = 0.02) and less beta-adrenergic blocker usage (p < 0.0001). Paraesophageal varices were detected in 97% of cirrhotic patients and 3% of control patients (p < 0.001) and were a more sensitive predictor of cirrhosis than varices at endoscopy (74%, p < 0.0001). Azygos vein and thoracic duct diameters, and gastric mucosa and submucosa thickness were greater for cirrhotic than control patients (p < 0.001). More hemorrhage patients had large (5 mm or greater) paraesophageal varices (odds ratio 3.1: 95% CI [1.1, 8.3]; p < 0.05) and paragastric varices (odds ratio 3.7: 95% CI [1.3, 10.2]; p = 0.01). Paraesophageal varix size correlated with ascites (p = 0.03) and, for nonhemorrhage patients, with Child's class (p < 0.01). CONCLUSIONS: Paraesophageal and paragastric varices correlate with the presence and severity of liver disease and portal hypertension. These data support the hypothesis that large paraesophageal and paragastric varices (5 mm or greater) may be risk factors for variceal hemorrhage, an observation that merits further prospective study. Cirrhosis causes dilation of the azygos vein and thoracic duct and thickening of gastric mucosa and submucosa.     

Patients with acute on chronic liver failure display "sepsis-like" immune paralysis

BACKGROUND/AIMS: Cellular immune depression is linked to high mortality in sepsis, but has yet to be systematically analysed in liver cirrhosis. The aim of the present study was to directly compare functional immune parameters in patients with acute on chronic liver failure (ACLF), severe sepsis, and non-decompensated cirrhosis. METHODS: Patients with ACLF (n=27) were investigated at admission to a medical ICU. Patients with stable liver cirrhosis (n=24) and severe sepsis (n=31) served as control groups. In all subjects, serum levels of IL-6 and IL-10, ex vivo production of TNF-alpha in a whole blood assay, and monocyte surface HLA-DR expression were determined. RESULTS: In patients with ACLF or sepsis, ex vivo TNF-alpha production and HLA-DR expression were severely decreased compared to subjects with stable cirrhosis (both P<0.001). Contrary, IL-6 levels were highest in septic patients, followed by subjects with ACLF and cirrhotic patients (both P<0.05). Immune dysfunction in ACLF was independent of aetiology of liver cirrhosis and associated with high mortality. CONCLUSIONS: Patients with ACLF and severe sepsis show a similar degree of cellular immune depression. The reduced cellular immune function in subjects with ACLF might contribute to the increased infectious morbidity of these patients and provide a rational basis for prevention strategies.     

Hemostatic effect of activated recombinant factor VII (rFVIIa) in liver disease: studies in an in vitro model

BACKGROUND/AIMS: There is clinical evidence for the efficacy of activated recombinant factor VII (rFVIIa) in patients with cirrhosis. The exact mechanism of action of rFVIIa in this clinical condition is unknown. We have explored effects of rFVIIa on hemostasis in cirrhotic patients using an in vitro perfusion technique. METHODS: Blood samples were drawn from control donors or from 11 patients previously diagnosed with cirrhosis (seven Child-Pugh B and four Child-Pugh C) and anticoagulated with low molecular weight heparin. rFVIIa was added to blood samples at therapeutic concentrations (0.5 or 1 microg/ml of plasma) and blood was recirculated through annular chambers containing damaged vascular segments. Presence of platelets and fibrin on the subendothelium were morphometrically quantified. RESULTS: Cirrhotic patients showed a diminished platelet interaction with the subendothelium compared to healthy donors (17.3% (9.28-28.88%) vs. 26.16% (19.96-54.5%), P<0.05). After addition of rFVIIa to cirrhotic samples, no differences in platelet covered surface were observed. However, fibrin formation was significantly improved after the addition of rFVIIa (from 51.81% (3.02-86.68%) to 86.94% (30.03-93.18%) and 89.05% (45.65-93.84%), respectively, P<0.05). CONCLUSIONS: Our data confirm a defective interaction of platelets with the subendothelium in cirrhotic patients. rFVIIa improved local fibrin formation at damaged sites and this mechanism could explain the beneficial action of rFVIIa in cirrhotic patients.     

The relationship of prorenin values to microvascular complications in patients with insulin-dependent diabetes mellitus

We have performed a cross-sectional analysis of the relationship between prorenin values and the microvascular complications of diabetes in a well controlled population of insulin-dependent diabetes mellitus (IDDM) subjects. One hundred and thirty-nine subjects (75 men, 64 women, age 44 +/- 17 years; duration of diabetes 19 +/- 15 years), formed the study group. Sixty-seven subjects (48.2%) had no complications, 55 (39.6%) had retinopathy alone, and 17 (12.2%) had retinopathy and albuminuria. Patients with no complications had lower prorenin values than those with microvascular complications (p < 0.001), whilst patients with both albuminuria and retinopathy had higher values than those with retinopathy alone (p < 0.05). Retinopathy was associated with duration of diabetes (p < 0.0001), diastolic blood pressure (p < 0.02) and albuminuria (p < 0.0001) while albuminuria was associated with prorenin (p < 0.02), serum triglyceride (p < 0.01) and retinopathy (p < 0.001). Patients with albuminuria were 5.5 times more likely to have raised prorenin values (>80 ng/mL/h) than those with normal albumin excretion [95% confidence interval (CI): 1.48-20.12] and those with retinopathy alone were 2.5 times as likely (95% CI: 1.19-5.15). Eighty patients with IDDM (40 males, 40 females; age: 47 +/- 17 years; duration of diabetes: 20 +/- 15 years), had retinal photography performed to determine the association between the severity of retinopathy and prorenin values. Retinopathy was more severe in patients with retinopathy and albuminuria than in those with retinopathy alone (p < 0.002). When the prorenin values of patients with more marked retinopathy (eye grade greater than 3) were compared, prorenin values of those with retinopathy and albuminuria were greater than those of patients with retinopathy alone [269 (139-1406) versus 91 (41-273) ng/mL/h: geometric mean (range); p < 0.05]. Furthermore, when patients without albuminuria were considered, there was no significant difference between the prorenin levels of patients with more severe retinopathy (eye grade >3) when compared to patients with lesser degrees of retinopathy [91 (41-273) versus 69 (23-375). In patients with microvascular complications, prorenin values were independently predicted by albuminuria (p < 0.0001) and diastolic blood pressure (p < 0.02) but not the severity of retinopathy. In conclusion, prorenin values are significantly associated with the presence of microvascular complications in patients with IDDM. The association with albuminuria may be stronger than the association with retinopathy.     

Risk factors for ocular surface disorders in patients with diabetes mellitus

OBJECTIVE: To evaluate risk factors for ocular surface disorders and tear dysfunction in patients with type 2 diabetes. STUDY DESIGN AND METHODS: This prospective case controlled study included 41 patients with type 2 diabetes and 20 healthy subjects as the control group. All subjects underwent routine ophthalmic examination, tear film break-up time (BUT) test, Schirmer test, fluorescein dye test, rose bengal staining test, and a questionnaire for subjective complaints. The relationship of metabolic control of diabetes mellitus, duration of diabetes, severity of diabetic retinopathy, and argon laser photocoagulation (ALP) to tear dysfunction was evaluated. RESULTS: Tear film BUT and Schirmer test values were significantly lower in diabetic patients compared with control subjects (P < 0.001). In the diabetic group, significantly more subjects had abnormal fluorescein and rose bengal staining than in the control group (P < 0.001). Abnormal tear function tests were associated with poorer metabolic glucose control, panretinal ALP, and proliferative diabetic retinopathy (P < 0.05), but not with duration of diabetes (P > 0.05). CONCLUSIONS: The results of the study indicate that poor metabolic control, panretinal ALP, and proliferative diabetic retinopathy are high risk factors for ocular surface disorders in type 2 diabetes. These patients should be followed more carefully, and should be referred to an ophthalmologist when required.     

Circulating endogenous cannabinoid anandamide and portal, systemic and renal hemodynamics in cirrhosis.

BACKGROUND: Endocannabinoids may participate in the homeostasis of arterial pressure. Recently, anandamide, the most extensively studied endocannabinoid, has been proposed as a key mediator in the peripheral arterial vasodilation of cirrhosis. OBJECTIVES: To determine if circulating levels of anandamide are related to the extent of the peripheral arterial vasodilation, the severity of portal hypertension and the degree of liver and renal dysfunction of patients with cirrhosis. METHODS: Plasma levels of anandamide and several systemic, portal and renal hemodynamic parameters were determined in 18 patients with cirrhosis and eight healthy subjects (control group). RESULTS: Plasma levels of anandamide were elevated in patients compared to the control group (P<0.05), nevertheless, no differences between patients with ascites and well-compensated patients were found. There was no correlation between anandamide concentration and arterial pressure, cardiac output and systemic vascular resistance, Child-Pugh's score, portal pressure, renal vascular resistance, plasma renin activity or plasma aldosterone concentration. CONCLUSIONS: Circulating levels of anandamide are increased in cirrhotic patients. However, this elevation was unrelated to the extent of arterial vasodilation, the severity of portal hypertension or the degree of hepatic and renal dysfunction. Although a local hormonal action cannot be excluded, our results do not support a relevant contribution of this system in the hemodynamic disturbance of cirrhosis.     

Magnetization transfer contrast imaging of liver cirrhosis

BACKGROUND/AIMS: To test the feasibility of magnetization transfer contrast (MTC) imaging in the evaluation of liver cirrhosis. METHODOLOGY: Three normal volunteers and 22 cirrhotic liver patients (13 of them harbored hepatoma) were prospectively studied with on-resonance binomial pulsed MTC imaging using a 1.0 Tesla MR scanner. Both MTC and non-MTC images were acquired. The magnetization transfer (MT) effect (defined as: 1-signal intensity of MTC/signal intensity of non-MTC), was used as an indicator and was correlated with different disease status. Lesion-to-liver contrast of non-MTC versus MTC imaging was also compared. RESULTS: Chronic hepatitis and early fibrosis had a MT effect similar to that of the normal group. Frank cirrhosis had the strongest MT effect. Cirrhosis, when infiltrated by diffuse hepatoma, showed a significantly weaker MT effect than that of the normal group (p<0.05), early cirrhosis (P<0.005), and frank cirrhosis (p<0.05). Overall, the MT effects in these 22 patients were widely variable. There was no significant improvement in lesion contrast of MTC imaging when compared to that of non-MTC imaging due to complex signal attenuation behavior of either the background liver tissue or the tumor itself. CONCLUSIONS: The complex pathological change of the cirrhotic liver tissue may account for the wide variation of the MT effect and the compromised lesion contrast in cirrhotic patients. Caution should be taken when cirrhotic tissue has an unusually weak MT effect. Then, the possibility of a mixed disease process such as fatty metamorphosis or diffuse hepatoma should be highly suspected. Our experience shows that MTC imaging plays a potential role in the evaluation of the multi-facets of cirrhotic tissue change.