Melatonin prevents experimental liver cirrhosis induced by thioacetamide in rats

Abstract:  Liver cirrhosis is a critical stage of chronic liver diseases that can produce liver failure, portal hypertension and hepatocarcinoma. Sustained oxidative stress plays a key role in cell damage and fibrosis induced during liver cirrhosis. We evaluated the effect of oxidative stress regulation by melatonin on the development of parenchymal destruction and stellate cell activation in experimental liver cirrhosis. Melatonin was administered to rats with liver cirrhosis induced by thioacetamide (TAA) for 1 or 3 months. Liver injury was assessed by serological analysis, as well as hematoxylin-eosin staining and the in situ apoptosis detection assay in liver sections. Oxidative stress was evaluated by lipoperoxide and reduced glutathione levels, and by the measurement of catalase and superoxide dismutase activities in liver and serum respectively. The activation of stellate cells was evaluated by α -smooth muscle actin expression in liver sections. Our results showed that TAA induced oxidative stress with extensive tissue damage and enhanced α -smooth muscle actin expression in liver. Melatonin prevented the oxidative stress-related changes associated with TAA toxicity. In conclusion, the study showed that melatonin prevents the tissue damage and fibrosis associated with TAA-induced liver cirrhosis in rats.     

Haemodynamic effects of chronic octreotide and tetrandrine administration in portal hypertensive rats

Octreotide is an effective portal hypotensive drug in the control of variceal bleeding. Tetrandrine is a type of calcium channel blocker recently reported to reduce portal hypertension. The present study was undertaken to investigate the haemodynamic effects of octreotide and tetrandrine, alone and in combination, in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation. Portal hypertensive rats were allocated into one of the four groups: vehicle group (saline, 0.5 mL/day), octreotide group (100 μg/kg per 12 h), tetrandrine group (20 mg/kg per 12 h), and octreotide (100 μg/kg per 12 h) plus tetrandrine (20 mg/kg per 12 h) group. Tetrandrine or saline was administered by gavage, and octreotide by subcutaneous injection. The drug was given for 8 consecutive days, starting 1 day before ligation and continuing onwards. Haemodynamic parameters were measured thereafter, using the radioactive microsphere method. The portal venous pressure and portal tributary blood ?ow were signi?cantly reduced, while portal territory and renal vascular resistances were signi?cantly enhanced, by octreotide, tetrandrine, or octreotide plus tetrandrine in portal hypertensive rats, compared with the vehicle group. Our results showed that long-term administration of octreotide, tetrandrine, or octreotide plus tetrandrine led to portal hypotensive effects in portal hypertensive rats, but octreotide alone exerted better anti-hyperdynamic effects compared with tetrandrine alone. A combination of octreotide and tetrandrine offered no major bene?cial anti-hyperdynamic effects compared with octreotide alone.     

部分脾动脉栓塞术对肝硬化门静脉高压症血流动力学的影响

目的探讨部分脾动脉栓塞术（PSE）治疗肝硬化门静脉高压症的临床疗效及应用价值。方法 23例不同原因肝硬化门静脉高压患者行PSE治疗,PSE术前及术后1周、1、3、6个月彩色多普勒分别检测患者门静脉和脾静脉的内径、血流速度,计算血流量,并与PSE术前配对分析。结果术后各期患者脾静脉、门静脉血流速度及血流量较术前降低（P〈0.05）;脾静脉内径术后各期与术前相比明显缩小（P〈0.05）;而门静脉主干内径术后6个月内缩小不明显（P〉0.05）。结论 PSE能有效的降低门静脉压力。     

Hemodynamic changes of systemic,hepatic, and splenic circulation following triglycyl-lysin-vasopressin administration in alcoholic cirrhosis

Triglycyl-lysin-vasopressin is a long-acting vasopressin derivative which is under consideration for the treatment of acute variceal bleeding in cirrhosis. However, its splanchnic hemodynamic effects have not been investigated thoroughly. In 11 patients with alcoholic cirrhosis, systemic and splanchnic hemodynamics were evaluated before and 20–40 min after intravenous administration of 2 mg triglycyl-lysin-vasopressin. Following the drug administration, heart rate decreased by 10% and cardiac index by 22% on the average, respectively; mean arterial pressure increased by 14% and systemic vascular resistence index by 48%. Hepatic venous pressure gradient showed a marked and persistent fall, averaging 31%. Hepatic and splenic blood flow decreased by 31% and 56%, respectively. A significant correlation was found between the decrease in hepatic venous pressure gradient and in splenic blood flow. By contrast, the decrease in the hepatic venous pressure gradient was not significantly correlated to the decrease in hepatic blood flow or in cardiac index. We conclude that in patients with alcoholic cirrhosis, triglycyl-lysin-vasopressin decreases portal pressure as well as hepatic and splenic blood flows. The decrease in portal pressure was due to the decrease in splanchnic blood inflow and not to the decrease in cardiac index.This work was supported in part by a grant from the Italian Ministry of Education (National Project Liver Cirrhosis).     

The free portal pressure in awake patients with and without cirrhosis of the liver

ABSTRACT— The free portal pressure was measured by percutaneous transhepatic catheterization of the portal vein in 106 patients with cirrhosis of the liver and in 19 patients without liver disease and with normal portography. Patients with cirrhosis had a median portal pressure of 38 cmH₂O and patients without liver disease had a median portal pressure of 16 cmH₂O. Among the cirrhotic patients the free portal pressure showed no relationship to etiology of cirrhosis, ascites, variceal bleedings or extrahepatic shunting. The median portal pressure was significantly higher in patients with (40 cmH₂O) than without (30 cmH₂O) gastroesophageal varices (p<0.01). The pressure was not related to the size of the varices.     

Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats

AIM:To examine whether the administration of atorvastatin and rosuvastatin would prevent experimentallyinduced hepatic cirrhosis in rats.METHODS:Liver cirrhosis was induced by injections of thioacetamide(TAA).Rats were treated concurrently with TAA alone or TAA and either atorvastatin(1,10 and 20 mg/kg) or rosuvastatin(1,2.5,5,10 and 20 mg/kg) given daily by nasogastric gavage.RESULTS:Liver fibrosis and hepatic hydroxyproline content,in the TAA-treated group was significantly higher than those of the controls [11.5 ± 3.2 vs 2.6 ± 0.6 mg/g protein(P = 0.02)].There were no differences in serum aminotransferase levels in the TAA controls compared to all the groups treated concomitantly by statins.Both statins used in our study did not prevent liver fibrosis or reduce portal hypertension,and had no effect on hepatic oxidative stress.Accordingly,the hepatic level of malondialdehyde was not lower in those groups treated by TAA + statins compared to TAA only.In vitro studies,using the BrdU method have shown that atorvastatin had no effect of hepatic stellate cells proliferation.Nevertheless,statin treatment was not associated with worsening of liver damage,portal hypertension or survival rate.CONCLUSION:Atorvastatin or rosuvastatin did not inhibit TAA-induced liver cirrhosis or oxidative stress in rats.Whether statins may have therapeutic applications in hepatic fibrosis due to other etiologies deserve further investigation.     

Hemodynamic effects of one week of carvedilol administration on cirrhotic rats

Background Carvedilol is a nonselective β-blocker with α₁-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. The current study was undertaken to evaluate the possible mechanism of carvedilol on hemodynamics in cirrhotic rats with portal hypertension produced by common bile duct ligation. Methods Male Sprague-Dawley rats received either a sham operation or common bile duct ligation. Three weeks after surgery, both sham-operated and cirrhotic rats were randomly assigned to receive vehicle or carvedilol 5 mg · kg⁻¹ · 12 h⁻¹ by gastric gavage for 1 week. Hemodynamic measurements, serum biochemistry, serum nitrate/nitrite and 6-keto-PGF_1α levels, and aortic mRNA expression of eNOS and COX-1 were performed on the eighth day after drug administration. Results Carvedilol treatment did not affect serum biochemistry in either sham-operated or cirrhotic rats. In sham-operated rats, administration of carvedilol significantly decreased the heart rate without affecting other hemodynamic values. In contrast, in cirrhotic rats, administration of carvedilol significantly decreased the cardiac index, portal pressure, heart rate, and portal territory blood flow, and it significantly increased systemic and portal territory vascular resistances. The hepatocollateral resistance was significantly decreased, but the hepatic arterial blood showed no significant changes. In sham-operated rats treated with carvedilol, serum nitrate/nitrite and 6-keto-PGF_1α levels were not affected. In contrast, cirrhotic rats receiving carvedilol showed a significant decrease in serum nitrate/nitrite and 6-keto-PGF_1α levels, associated with a decrease in aortic mRNA expression of eNOS and COX-1 compared with those receiving vehicle. Conclusions Carvedilol decreased portal pressure through a reduction of splanchnic blood flow associated with a decrease in hepatocollateral resistance. Additionally, administration of carvedilol decreased endothelial-related vasodilatory activities.     

肝硬化诊治思路:经典与拓展

肝硬化是我国最严重的公共卫生问题之一。对失代偿期肝硬化患者及时进行病因治疗,延缓其发展,一直是实用而有效的经典策略。高质量或创新的诊疗其实就蕴含在这些平凡的细致工作中。门静脉高压本质上是血管疾病,及时解除门静脉系统压力是防止疾病进展和各种严重并发症的关键。治疗决策需要在对门静脉高压全局有全面了解的基础上做出,微创技术是完成智慧策略的重要手段。     

肝硬化后门静脉血栓形成的临床特点研究

目的研究肝硬化(liver cirrhosis,LC)后门静脉血栓(portal vein thrombosis,PVT)形成的临床特点。方法对9678例LC患者进行回顾性分析,采用腹部B超/腹部增强CT及腹部增强MRI检查门脉主干或左右分支,筛选出LC伴PVT形成者(PVT组),同时将LC后无PVT患者纳为对照组,比较2组的Child-Pugh分级、门静脉及脾静脉宽度、脾脏面积及厚度、腹水、上消化道出血、肝性脑病和肝肾综合征等并发症。结果 LC患者中有396例(4.09%)PVT形成。PVT组中LC的病因主要有乙型肝炎、酒精性及丙型肝炎LC,PVT主要分布在门静脉主干、门静脉右支、肠系膜上静脉、门静脉左支和脾静脉。按Child-Pugh进行分级,PVT组与对照组比较,肝损伤较重(P<0.01)。PVT组合并腹水、上消化道出血、肝性脑病及肝肾综合征等并发症的发病率均较对照组高(P<0.01)。PVT组门静脉和脾静脉宽度分别为(1.50±0.23)cm和(1.25±0.34)cm,对照组为(1.38±0.23)cm和(1.06±0.29)cm。PVT组脾脏面积为(97.48±32.90)cm2,脾脏厚度为(6.09±1.21)cm;对照组分别为(81.19±29.10)cm2和(5.26±0.99)cm。PVT组门静脉及脾静脉宽度和脾脏厚度均大于对照组,差异有统计学意义(P<0.05)。PVT组有侧支循环开放的患者占96.21%,对照组为78.25%,2组比较差异有统计学意义(P<0.05)。结论 LC后PVT形成对LC患者的临床转归有重要影响。     

Erectile dysfunction in cirrhosis is impacted by liver dysfunction,portal hypertension,diabetes and arterial hypertension

Background

Although several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function‐5 (IIEF‐5) is a well‐validated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis.

Methods

In this prospective study, erectile dysfunction was defined as: absent (>21 IIEF‐5‐points), mild (12‐21) and severe (5‐11). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded.

Results

Among n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 ± 9 years; model for end‐stage liver disease score (MELD): 12.7 ± 3.9; Child‐Pugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mild‐to‐moderate and moderate‐to‐severe erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). Child‐Pugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, beta‐blocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.16‐34.85]; P = .033), diabetes (OR: 7.40 [1.31‐41.75]; P = .023), MELD (OR: 1.19 [1.03‐1.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.002‐1.23]; P = .045) were independent risk factors for the presence of erectile dysfunction.

Conclusion

About two‐thirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.     

Relationships between the severity of cirrhosis and haemodynamic values in patients with cirrhosis

Abstract The relationship between the severity of cirrhosis and systemic and hepatic haemodynamic values was evaluated in 193 patients with cirrhosis, most of whom were diagnosed with post-necrotic cirrhosis. It was found that the hepatic venous pressure gradient and cardiac output in Pugh's A patients (13.6 ± 4.8 mmHg and 6.2 ± 1.6 L/min, mean ± s.d.) were significantly lower than in both Pugh's B (16.8 ± 4.3 mmHg and 7.3 ± 2.1 L/min) and Pugh's C (18.8 ± 5.5 mmHg and 7.4 ± 2.3 L/min) patients ( P < 0.01), respectively. In contrast, the systemic vascular resistance in Pugh's A patients (1232 ± 369 dyn/s per cm⁵) was significantly higher than in both Pugh's B (1016 ± 345 dyn/s per cm⁵) and Pugh's C (935 ± 234 dyn/s per cm⁵) patients ( P < 0.01), respectively. Additionally, not only was there a positive correlation found between Pugh's score and cardiac output and hepatic venous pressure gradient, but a negative correlation was found between Pugh's score and systemic vascular resistance. It was also confirmed that the degree of portal hypertension and the hyperdynamic circulation were more severe in patients with ascites than in those without ascites. However, there were no statistically significant differences in hepatic venous pressure gradient among patients with F1, F2 and F3 esophageal varices (15.7 ± 4.0, 17.0 ± 4.8 and 18.0 ± 4.8 mmHg, respectively). It is concluded that in those patients with cirrhosis, the severity of cirrhosis is closely related to the degree of the hyperkinetic circulatory state and portal hypertension.     

Relationship between degree of portal hypertension and liver histologic lesions in patients with alcoholic cirrhosis

The relationship between the degree of portal hypertension and histologic liver lesions was studied in a group of 84 patients with histologically proven alcoholic cirrhosis. The degree of portal hypertension was evaluated by the gradient between wedged and free hepatic venous pressures. Five histologic lesions were quantified: liver cell necrosis, Mallory bodies, neutrophilic infiltrate, fibrosis, and fatty infiltration. The gradient between wedged and free hepatic venous pressures was significantly correlated with the degree of liver cell necrosis and the degree of neutrophilic infiltrate. The stepwise regression analysis showed that only liver cell necrosis has a significant and independent correlation for the degree of portal hypertension. The value for the gradient between wedged and free hepatic venous pressures was significantly higher in patients with (N=48) than in those without (N=36) acute alcoholic hepatitis (19.4±0.8 and 16.5±0.7 mmHg, respectively). Thus, histologic liver lesions observed in acute alcoholic hepatitis may play a role in the risk of complications of portal hypertension in patients with alcoholic cirrhosis.     

A canine portal hypertension model induced by intra‐portal administration of Sephadex microsphere

Background and Aim: Big animal models of portal hypertension are important for the research into this disease. The aim of this study was to establish a canine portal hypertension model by intra‐portal administration of microspheres. Methods: Sixteen mongrel dogs were assigned to control group and experimental group randomly. The catheterization of portal vein was performed by laparotomy and the outer end of the catheter was fixed subcutaneously in the abdominal wall. The dogs of the experimental group were given intra‐portal injections of microspheres at a five‐day interval, six times in total. Portal hemodynamics, blood cell counting, liver and renal function test, portography, gastroscopy, liver, spleen and lung histological examination were taken to evaluate the model. Results: 1, 2, 3 and 4 months after initial injection of microspheres, portal venous pressure rose from baseline 8.7 ± 0.7 mmHg to 24.3 ± 1.6, 20.6 ± 2.1, 19.0 ± 1.8 and 17.7 ± 2.0 mmHg, respectively (P < 0.01). The diameter of portal vein increased from 7.6 ± 0.3 to 8.6 ± 0.3 mm, calculated portal resistance increased from 0.46 ± 0.06 to 1.06 ± 0.20 (mmHg/mL/min/kg body weight); velocity of portal blood flow decreased from 35.1 ± 1.7 to 26.1 ± 2.4 cm/s (P < 0.01, respectively). The animals of experimental group developed marked splenomegaly and profuse portosystemic collateral circulations with normal liver and renal function. Conclusion: Repeated intra‐portal administration of microspheres can induce stable and reproducible chronic portal hypertension in dogs with normal liver and renal functions. This model can meet multiple demands of both basic and clinical research of portal hypertension.     

Changes of hepatic and systemic haemodynamics following somatostatin administration in patients with hepatitis B-related cirrhosis

Abstract Somatostatin has been used to effectively control acute variceal haemorrhage, with conjectured mechanisms on portal hypertension. We, therefore, evaluated the effects of somatostatin on hepatic and systemic haemodynamics in 15 patients with hepatitis B-related cirrhosis and portal hypertension. All patients received an intravenous, continuous infusion of somatostatin 250 μg/h, following a bolus injection of 250 μg. In systemic haemodynamics, the mean arterial pressure (MAP) increased ( P < 0.05), associated with a reflex bradycardia within 3 min following bolus injections, compared with basal values. The right atrial pressure, pulmonary capillary wedge pressure, inferior vena cava pressure, cardiac index, and systemic vascular resistance remained unaffected after drug infusion. In hepatic haemodynamics, the wedge hepatic vein pressure remained unchanged after drug administration. However, there was an increase in free hepatic vein pressure (FHVP; P < 0.05), and a trend toward a decrease in the hepatic vein pressure gradient (HVPG; P = 0.063), within 3 min after bolus injection. Furthermore, the hepatic blood flow decreased significantly at 10 and 30 min after somatostatin infusion ( P < 0.05). The effective sinusoidal perfusion assessed by indocyanine green infusion also decreased progressively at 10 min ( P = 0.057) and 30 min ( P < 0.05). We concluded that somatostatin, at the dose used in this study, caused a transient and bolus-related vasoconstrictive effect, resulting in increases in MAP and FHVP, a decrease in heart rate, and a trend toward lower HVPG. In addition, somatostatin reduced the hepatic blood flow and effective sinusoidal perfusion which may be hazardous to cirrhotic patients during variceal haemorrhage.     

肝硬化患者血栓前状态分子标志物对门静脉血栓形成的监测意义

目的探讨肝硬化患者及肝硬化合并门静脉血栓患者血栓前状态分子标志物的变化。方法将32例河南省濮阳市油田总医院2011年-2013年住院的肝硬化合并门静脉血栓的患者设为血栓组(PVT组),40例肝硬化非门静脉血栓的患者设为非血栓组(非PVT组),采用ELISA法检测血小板颗粒膜蛋白-140(GMP-140)、血管性假性血友病因子(v WF:Ag)、血栓调节蛋白(TM)、D二聚体(DD)的含量并进行分析。计量资料组间比较采用t检验。结果 PVT组GMP-140、TM、v WF:Ag、DD含量分别为(20.68±1.49)μg/L、(47.24±1.36)μg/L、(194.32±7.68)%、(0.86±0.12)mg/L,均明显高于非PVT组(13.05±0.97)μg/L、(34.05±5.03)μg/L、(136.21±3.68)%、(0.42±0.08)mg/L,两组比较差异均有统计学意义(P值均0.01),PVT组伴中重度食管静脉曲张患者血浆GMP-140、TM、v WF:Ag、DD水平分别为(19.68±1.29)μg/L、(45.24±1.26)μg/L、(196.32±6.68)%、(0.79±0.12)mg/L,显著高于轻度食管静脉曲张患者(12.05±1.07)μg/L、(35.05±4.83)μg/L、(141.21±3.45)%、(0.36±0.08)mg/L,差异均有统计学意义(P值均0.01);PVT组伴消化道出血患者血浆GMP-140、TM、v WF:Ag、DD水平分别为(18.98±1.18)μg/L、(46.78±1.35)μg/L、(197.32±6.39)%、(0.81±0.14)mg/L显著高于无出血患者(11.98±1.12)μg/L、(36.02±4.78)μg/L、(138.21±4.12)%、(0.35±0.12)mg/L,差异均有统计学意义(P值均0.01)。结论血栓前状态分子标志物水平可能对肝硬化门静脉血栓形成有监测作用。     

Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis

The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 g/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution–TTU method. Acute administration of vapreotide significantly decreased SRS BF (–17.3 ± 19 vs –1.1 ± 14%, P < 0.05) and portal pressure (–8 ± 9 vs 0 ± 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 ± 1.5 vs 1.2 ± 1.0 ml/min, P < 0.05) and cardiac index (50 ± 15 vs 33 ± 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.     

Haemodynamic effects of chronic tetrandrine treatment in portal hypertensive rats

Tetrandrine is a calcium channel antagonist with reported antihypertensive effect. However, the potential role of tetrandrine as a therapeutic agent in portal hypertension has yet to be explored. The present study aimed to investigate the haemodynamic effects of chronic tetrandrine treatment on portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Animals were allocated into one of two groups: a tetrandrine group and a vehicle group. Tetrandrine (20 mg/kg) or vehicle was administered by gavage every 12 h for 8 consecutive days, starting 1 day before ligation and continuing thereafter. After 8 days of tetrandrine treatment, systemic haemodynamics, organ blood flows and the degree of portal-systemic shunting were measured after an overnight fast. The portal venous pressure and portal tributary blood flow were significantly decreased, while portal territory as well as hepato-collateral vascular resistance significantly increased in the tetrandrine group compared with the vehicle group. The cardiac index was increased, while systemic vascular resistance was decreased, in the tetrandrine group. Mean arterial pressure, heart rate, portalsystemic shunting and bodyweight were similar between the two groups. Renal blood flow was decreased in the tetrandrine group. In conclusion, long-term treatment of tetrandrine reduced portal venous pressure and alleviated splanchnic hyperaemia in portal hypertensive rats without affecting the portal-systemic shunting.     

Altered basal and postprandial plasma melatonin, gastrin, ghrelin, leptin and insulin in patients with liver cirrhosis and portal hypertension without and with oral administration of melatonin or tryptophan

Abstract:  This investigation was designed to assess the effects of oral administration of melatonin (10 mg) and tryptophan (Trp) (500 mg) on fasting and postprandial plasma levels of melatonin, gastrin, ghrelin, leptin and insulin in 10 healthy controls and in age-matched patients with liver cirrhosis (LC) and portal hypertension. Fasting plasma melatonin levels in LC patients were about five times higher (102 ± 15 pg/mL) than in healthy controls (22 ± 3 pg/mL). These levels significantly increased postprandially in LC patients, but significantly less so in controls. Treatment with melatonin or l -Trp resulted in a further significant rise in plasma melatonin, both under fasting and postprandial conditions, particularly in LC patients. Moreover, plasma gastrin, ghrelin, leptin and insulin levels under fasting and postprandial conditions were significantly higher in LC subjects than in healthy controls and they further rose significantly after oral application of melatonin or Trp. This study shows that: (a) patients with LC and portal hypertension exhibit significantly higher fasting and postprandial plasma melatonin levels than healthy subjects; (b) plasma ghrelin, both in LC and healthy controls reach the highest values under fasting conditions, but decline postprandially, especially after oral application of melatonin or Trp; and (c) plasma melatonin, gastrin, ghrelin and insulin levels are altered significantly in LC patients with portal hypertension compared with that in healthy controls possibly due to their portal systemic shunting and decreased liver degradation.