Gastric vascular ectasias in cirrhosis: association with hypoacidity not related to gastric atrophy

To investigate whether hypergastrinemia and low serum levels of pepsinogen I are associated with gastric hypoacidity in cirrhosis with capillary ectasia of gastric mucosa and whether this alteration is secondary to the presence of atrophic gastritis, two groups of patients were studied: 1) 12 cirrhotic patients with diffuse gastric red spots at the endoscopic examination, and 2) 12 cirrhotic patients with endoscopically normal mucosa. Vascular ectasia of the gastric mucosa was histologically confirmed in all patients with gastric red spots. The study of base-line and stimulated acid gastric secretion showed that 9 of 12 (75%) cirrhotics with gastric vascular ectasia had achlorhydria and that 8 of these 9 patients had high base-line gastrin serum levels (greater than 130 pg/ml) and low base-line pepsinogen I serum levels (less than 20 ng/ml). Base-line gastrin and pepsinogen I serum levels were significantly greater and lower, respectively, in patients with gastric vascular ectasias than in cirrhotics without these lesions. None of the patients of either group had complete atrophy in the corpus of the stomach, and only 4 of the 9 cirrhotics with gastric vascular ectasia and achlorhydria had moderate atrophy. These results show that achlorhydria is frequently associated with hypergastrinemia and low pepsinogen I serum levels in patients with cirrhosis and gastric vascular ectasias and suggest that this disturbance is not secondary to a morphologic abnormality of the gastric mucosa.     

Gastric mucosal vascular ectasias causing bleeding in cirrhosis. A distinct entity associated with hypergastrinemia and low serum levels of pepsinogen I

To characterize bleeding from gastric red spots in patients with cirrhosis, three groups of patients were studied: (a) 11 cirrhotic patients bleeding from gastric red spots, (b) 18 nonbleeding cirrhotic patients without gastric red spots, and (c) 13 noncirrhotic patients with endoscopic normal mucosa (controls). Histologic examination of antral biopsy specimens revealed a diffuse capillary ectasia without inflammation in 8 of the 11 cirrhotic patients with gastric lesions. Morphometric analysis disclosed a significantly greater mean mucosal capillary cross-sectional area in cirrhotic patients with gastric lesions (mean +/- SE, 1371 +/- 320 microns2) than in those without gastric lesions (541 +/- 61 microns2) (p less than 0.005) or controls (353 +/- 20 microns2) (p less than 0.001). Hypergastrinemia was detected in 8 of the 11 cirrhotic patients with lesions, in 2 of the 18 cirrhotic patients without gastric lesions, and in none of the controls (p less than 0.001). Gastrin serum levels correlated significantly (r = 0.80) with mean mucosal capillary cross-sectional area in patients with cirrhosis. Pepsinogen I serum levels below 20 ng/ml were observed in 7 of the 11 cirrhotic patients with lesions, in 1 of the 18 cirrhotic patients without lesions, and in none of the controls. These data indicate that bleeding from gastric red spots in patients with cirrhosis is a distinct entity characterized by vascular ectasia of the gastric mucosa. This condition seems to be associated with hypergastrinemia and low serum levels of pepsinogen I.     

Gastric Epithelial Cell Proliferation in Patients with Liver Cirrhosis

An increased risk for gastric cancer in patients with liver cirrhosis has recently been reported. This study was performed in order to determine gastric epithelial cell proliferation in cirrhotic patients and to evaluate the role of congestive gastropathy (CG) and Helicobacter pylori infection in this process. Thirty-six cirrhotic patients and 18 controls were enrolled in the study. All patients underwent endoscopy and three biopsies were performed in the antrum and three in the gastric body. The presence of H. pylori infection was assessed by a rapid urease test and histology. The antral biopsies were used for gastric cell proliferation assessment by an immunohistochemical analysis (Ki-67). There was no significant difference in epithelial cell proliferation between cirrhotics and controls. Gastric proliferation values were higher in patients with H. pylori infection compared with uninfected patients, both in cirrhotic (P = 0.003) and in control groups (P = 0.06). Among the cirrhotic group, we found a progressive increase in gastric cell proliferation values related to the degree of CG, the highest values being observed in cirrhotic patients with severe CG. Moreover, cirrhotics with both severe CG and H. pylori infection had the highest proliferation values when compared with all other subgroups. In conclusion, this study found that: (1) CG significantly affects epithelial cell proliferation in gastric mucosa in cirrhotic patients, (2) H. pylori infection plays a similar role in gastric cell proliferation in both cirrhotic and non-cirrhotic patients, and (3) CG and H. pylori could act synergistically in this process.     

Helicobacter pylori infection in dyspeptic cirrhotic patients

BACKGROUND/AIMS: To date, few studies have focused on the role of Helicobacter pylori (H. pylori) in cirrhotic patients with gastroduodenal disease and reported results are conflicting. The aim of this study was to assess the H. pylori infection rate in dyspeptic cirrhotic patients with or without gastroduodenal lesions at endoscopy. METHODOLOGY: In a prospective study, 226 consecutive dyspeptic cirrhotic patients were enrolled in the study upon assessment of H. pylori infection. Two-hundred dyspeptic non-cirrhotic patients were also included as controls. The presence of H. pylori was detected by rapid urease test and histology (Giemsa staining) in 3 biopsy specimens from the antrum and 3 from the gastric body. RESULTS: H. pylori infection was found in 135 (59.7%) cirrhotics and in 121 (60.5%) controls (p = NS). The prevalence of gastric ulcer was higher in cirrhotics than in controls (16% vs. 2.5%, p = 0.0001), while the prevalence of duodenal ulcer was similar (11% vs. 12%, respectively). The H. pylori infection rate was similar between cirrhotics and controls, both with gastric (83% vs. 80%) and with duodenal (88% vs. 96%) ulcers. Moreover, in our study, a H. pylori-related peptic lesion was the cause of previous gastroduodenal bleeding in 6 of 50 (12%) cirrhotic patients. CONCLUSIONS: Our results indicated that H. pylori infection is implicated in the pathogenesis of peptic ulcer in cirrhotic patients, similar to findings in non-cirrhotic patients.     

Prostaglandin E2 and prostaglandin F2 alpha biosynthesis in human gastric mucosa: effect of chronic alcohol misuse.

BACKGROUND AND AIMS: The results of experimental studies support the hypothesis that decreased prostaglandin production might play a part in the gastric mucosal injury induced by alcohol. In this study, it was investigated whether alcohol misuse impairs the synthesis of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) in gastric mucosa. PATIENTS: Fifty six alcoholic patients and 66 subjects without alcohol misuse were included in the study. METHODS: Mucosal biopsy specimens were obtained from the antrum and body of the stomach. Maximal synthesis rates of PGE2 and PGF2 alpha were determined in the microsomal fraction of the biopsy specimens. RESULTS: The rates of synthesis of both prostaglandins in biopsy specimens from the antrum were not significantly different from those obtained in the body. Synthesis of both prostaglandins was significantly reduced in alcoholic patients who abstained less than five days compared with the non-alcoholic group with normal mucosa (PGE2-40%, PGF2 alpha-42% respectively). In non-alcoholic patients with severe gastritis PGE2 synthesis was increased (+30%, p < 0.05) and PGF2 alpha synthesis was decreased (-42.5%, p < 0.025). In alcoholic patients with severe gastritis PGE2 synthesis was depressed by almost 60% (p < 0.001) compared with the non-alcoholic group with severe gastritis. Neither colonisation of Helicobacter pylori nor smoking had a significant influence on the prostaglandin synthesis. CONCLUSIONS: Chronic alcohol misuse is associated with significantly reduced capacity for prostaglandin synthesis in gastric mucosa and this alcohol induced decrease in prostaglandin synthesis is modulated by the presence and degree of gastritis.     

Gastric mucosal histamine in duodenal-ulcer patients: release by secretin.

In 5 duodenal-ulcer patients with anaphylactic skin reaction to intradermal secretin and in 4 healthy controls, biopsy samples from the fundic region of the stomach were superfused with phosphate buffer alone and with phosphate buffer containing 20 C.U./ml synthetic secretin. In response to secretin, the mucosa from duodenal-ulcer patients released significantly increasing amounts of histamine (P is less than 0.05) whereas control tissue did not respond. Additionally, in duodenal-ulcer patients the histamine content of untreated gastric mucosa was about twice as high as in controls (P is less than 0.02). It is suggested that the elevated mucosal histamine could account for the basal and stimulated gastric hypersecretion of duodenal-ulcer patients. In addition, the results are compatible with the concept that in a certain type of duodenal ulceration, secretin does drive rather than inhibit gastric secretion.     

Elevated growth hormone levels and insulin resistance in patients with cirrhosis of the liver

Carbohydrate intolerance is frequently seen in patients with hepatic cirrhosis. To study the role of the counter regulatory hormones, glucagon, cortisol and growth hormone in this disease, these hormones were measured in 11 patients with hepatic cirrhosis and six controls during a 4-hour oral glucose tolerance test (OGTT) and in five normal and cirrhotic subjects during steady-state plasma insulin and glucose concentrations (SSPGI) achieved with the euglycemic clamp technique. Fasting plasma glucose was 103 +/- 4.3 mg/dl in cirrhotics and 88 +/- 3.3 mg/dl in controls (p less than 0.001). Immunoreactive insulin (IRI) was 24.3 microU/ml in cirrhotics and 12.7 +/- 2.2 microU/ml in controls (p less than 0.001); immunoreactive glucagon (IRG) was 263 +/- 30 pg/ml in cirrhotics and 122 +/- 17.5 pg/ml in controls (p less than 0.001); serum growth hormone (GH) was 4.4 +/- 0.9 ng/ml in cirrhotics and 0.5 +/- 0.1 ng/ml in controls (p less than 0.001). During OGTT, the 2-hour glucose concentration was 201 +/- 9.7 mg/dl in cirrhotic subjects and 147 +/- 10.0 mg/dl in controls (p less than 0.001). IRG levels were suppressed by 20% of basal values in patients with cirrhosis, while controls showed 10% suppression after an oral glucose load. At 60 minutes, the serum GH was 14.7 +/- 3.9 ng/ml in cirrhotics and 0.3 +/- 0.1 ng/ml in controls (p less than 0.001). The normal suppressive effect of hyperglycemia on GH secretion in controls was sharply contrasted by a paradoxical elevation of serum GH in the cirrhotic group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Consequences of hyperglycemia on glucose and nitrogen metabolism in liver cirrhosis. A study using a hyperglycemic clamp

To study the consequences of hyperglycemia on glucose and nitrogen metabolism in cirrhosis, an hyperglycemic clamp was performed in 5 cirrhotic patients and 5 normal controls during two subsequent periods of 90 min, at 7.78 and then at 13.89 mmol/l. In the first period, glucose infusion and metabolic clearance rates were decreased in cirrhotics vs controls (p less than 0.05). In the second period, this difference between the two groups disappeared because of a more important enhancement in cirrhotics. Baseline plasma C peptide levels and those during hyperglycemia were the same during hyperglycemia in both groups, but plasma insulin level rose more in cirrhotics (p less than 0.05). Baseline insulin secretion following IV glucagon was reduced in cirrhotics vs controls (p less than 0.05), but became normal in the hyperglycemic state. Plasma glucagon levels were enhanced at all times in cirrhotics vs controls (p less than 0.01), but dropped more in cirrhotics vs controls (p less than 0.05). Insulin responsiveness, defined as the "glucose consumption: plasma insulin concentration" ratio was reduced in cirrhotics at 7.78 mmol/l (p less than 0.01), but was the same in both groups at 13.80 mmol/l because of a more important enhancement in cirrhotics, reflecting an improvement of insulin action probably at the post-receptor level and of non-insulin-mediated glucose transport. Hyperglycemia induced a drop in plasma concentration and muscular release of all aminoacids, excepted alanine, between the basal state and the end of the study. Aminoacid concentration rose only in cirrhotics, without any change in muscular output. In the same time, blood ammonia level rose only in cirrhotics, without reduction of muscular uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastric and gall bladder emptying of a mixed meal are not coordinated in liver cirrhosis--a simultaneous sonographic study.

BACKGROUND AND AIM: An impaired contractility has been suggested as a contributor to the increased incidence of gallstones in liver cirrhosis, but the few studies on gall bladder emptying in cirrhotics offered contradictory results. Ingestion of a meal triggers the physiological pathway of gall bladder emptying; therefore, it was decided to analyse postprandial kinetics by investigating simultaneously the rates of gastric and gall bladder emptying of a mixed meal in patients with liver cirrhosis. METHODS: Gastric and gall bladder emptying were measured using ultrasound techniques after a solid-liquid meal (14 g fat, 425 kcal) in 24 patients with liver cirrhosis and in 12 controls. None of the subjects had gall bladder disease. Sequential changes in cross sectional area of the gastric antrum and in gall bladder volume were represented as a monoexponential process after the test meal. Cirrhotic patients were analysed according to the severity of disease (Child classes). The presence of portal gastropathy was assessed by endoscopy. Differences between groups were assessed using the two tailed Student's t test for unpaired observations and the correlations by linear regression (Pearson's coefficient). RESULTS: It was found that gastric emptying after the solid-liquid meal was delayed in cirrhotic patients compared with controls. Gall bladder emptying was significantly diminished in cirrhotic patients: the area under curve was greater in Child A (p = 0.01), Child B (p = 0.04), and Child C (p = 0.014) cirrhotics compared with controls. No correlation was found between the variables of gastric and gall bladder emptying. Gall bladder refilling began earlier in cirrhotics than in controls, before completion of gastric emptying. CONCLUSIONS: These results indicate the lack of coordination between gastric and gall bladder emptying in liver cirrhosis. They also support the hypothesis that diminished gall bladder contractility might contribute to the increased gallstone formation in liver cirrhosis.     

Gastric acid secretion and gastrin and gastric inhibitory polypeptide release in cirrhotic patients

Gastric acid secretion, incidence of gastric mucosal lesion, and gut hormone responses were studied in 24 patients with liver cirrhosis. Gastric acid output in these subjects showed normal acidity and was nearly similar to that in patients with gastric ulcer. The incidence of gastric mucosal lesion was high, especially in patients whose plasma disappearance rate of indocyanine green was low. Plasma levels of both gastric and gastric inhibitory polypeptide were higher in cirrhotic patients than in control subjects both in the fasting state and after the ingestion of a test meal. Gel chromatography of the postprandial plasma of cirrhotics showed a higher immunoreactivity at the second peak than in controls. This is because cirrhotics have a higher percentage of authentic gastric inhibitory polypeptide, although the elution patterns were similar in both groups. It is suggested that impairment of extraction of some molecular components of both gastric and gastric inhibitory polypeptide may occur in the cirrhotic liver.     

Increased gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy.

To characterize gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy, 34 cirrhotics with this lesion and 24 noncirrhotics were studied by reflectance spectrophotometry and laser-Doppler flowmetry during endoscopy. A significant correlation was observed between the hemoglobin content of the gastric mucosa, measured by reflectance spectrophotometry, and the serum hemoglobin concentration both in cirrhotics (r = 0.72) and in noncirrhotics (r = 0.87). IHb ratio (hemoglobin content of gastric mucosa divided by blood hemoglobin concentration) was higher in cirrhotics with portal hypertensive gastropathy than in noncirrhotics (P < 0.001), whereas the oxygen content of the gastric mucosa was similar in both groups. This pattern indicates that cirrhotics with portal hypertensive gastropathy have increased gastric perfusion without congestion. Gastric blood flow estimated by laser-Doppler was significantly higher in cirrhotics with portal hypertensive gastropathy than in noncirrhotics (P < 0.001). In cirrhotic patients, gastric areas with cherry red spots showed a significantly higher IHb ratio than areas with a mosaic or scarlatina pattern (P < 0.05). The magnitude of changes in gastric perfusion and the endoscopic severity of portal hypertensive gastropathy had no relationship with the degree of portal hypertension or the azygos blood flow.     

肝硬化患者胃黏膜前列腺素E2的研究

目的研究肝硬化患者胃黏膜前列腺素E2(PGE2)及意义。方法选取肝硬化患者60例及慢性胃炎、非溃疡性消化不良(NUD)患者各80例,行上消化道内镜检查,取胃窦及胃体各1块黏膜组织,用RIA法检测PGE2含量。结果(1)肝硬化组胃黏膜PGE2含量明显低于慢性胃炎及NUD组。(2)在肝硬化患者中,胃黏膜PGE2含量门脉高压胃病(PHG)组明显低于非PHG组,肝源性溃疡(HU)组亦明显低于非HU组,而与肝功能分级无关。结论(1)肝硬化胃黏膜防御机制减弱。(2)肝硬化胃黏膜PGE2的异常参与PHG及HU的形成。     

Clinical Characterization of Gastric Antral Vascular Ectasia: A Potential Manifestation of the Metabolic Syndrome

Background and ObjectivesGastric antral vascular ectasia is a relatively common endoscopic finding. Past studies have shown an association of gastric antral vascular ectasia with cirrhosis and autoimmune disorders. We aimed to re-examine these associations and to investigate a possible association of gastric antral vascular ectasia with features of the metabolic syndrome.MethodsThere were 135 patients with a diagnosis of gastric antral vascular ectasia from years 1995-2013 seen at the University of Virginia who were identified from a clinical data repository and age and sex matched to a cohort of patients without gastric antral vascular ectasia undergoing endoscopy within the same time frame as the index cases. The groups were compared for comorbidities including autoimmune disease, cirrhosis, vascular disease, body mass index (BMI), diabetes mellitus, and cirrhosis due to nonalcoholic steatohepatitis.ResultsSixty-four percent of gastric antral vascular ectasia patients were cirrhotic, compared with 14% of controls (P <.001). Vascular disease was more common in the gastric antral vascular ectasia cohort (57% vs 36%; P <.001). The mean BMI was also higher in the gastric antral vascular ectasia cohort (33.7 kg/m² vs 28.8 kg/m²; P <.001). Diabetes mellitus and nonalcoholic steatohepatitis cirrhosis were more frequently observed in gastric antral vascular ectasia subjects (64% vs 29% in controls [P <.001] and 28% vs 2% [P <.001], respectively). There was not an increased prevalence of autoimmune disease in gastric antral vascular ectasia patients vs controls (15% vs 13%; P = .861).ConclusionThese results confirm the association of gastric antral vascular ectasia with underlying cirrhosis and revealed a significant correlation of gastric antral vascular ectasia with features of metabolic syndrome such as diabetes, BMI, vascular disease, and nonalcoholic steatohepatitis cirrhosis. The pathophysiology of gastric antral vascular ectasia remains uncertain, but we speculate that it may be a manifestation of the metabolic syndrome.     

Gastric motility in patients with presinusoidal portal hypertension

OBJECTIVE: The aim of this study was to evaluate the consequences of portal hypertension (PH) for the motor functions of the human stomach. METHODS: The PH model used was the hepatosplenic form of mansonic schistosomiasis, as this is a condition characterized by PH but with considerably preserved hepatocellular function. The study included 15 patients with PH and 25 healthy volunteers who served as controls. The adaptive relaxation of the stomach was studied in 12 patients with PH and in 10 controls by a manometric method during rapid insufflation (25-30 s) of 700 ml of air into the gastric fundus. The gastric emptying of a liquid solution (15 patients with PH and 20 controls) and of a solid-liquid meal (nine patients with PH and 12 controls) was determined by gamma scintigraphy. The thickness of the gastric antrum wall was measured by ultrasonography in 12 patients with PH and in 10 controls. RESULTS: Patients with PH showed the following: 1) reduction of the adaptive relaxation of the stomach (p < 0.0001); 2) acceleration of gastric emptying of the test solution (T 1/2, p = 0.0316), which became particularly expressive 25, 30, 40, and 50 min after ingestion (p = 0.0181, 0.0215, 0.0181, and 0.0215, respectively); 3) no alteration in gastric emptying of the solid-liquid meal as judged by T 1/2 values (p = 0.9170) or lag-phase values (p = 0.7544); and 4) a conspicuous increase in gastric wall thickness as determined by antrum wall measurements (p = 0.0008). CONCLUSIONS: The reduced gastric adaptive relaxation demonstrated in patients with PH and normal hepatocellular function leads us to consider this condition as a cause of diastolic dysfunction of the stomach. In this disease, the motor alteration may be explained as a consequence of the reduction of gastric wall compliance, probably resulting from edema and vascular ectasia, which were indirectly detected by the increase thickness of the gastric antrum wall. The discrete acceleration of liquid gastric may be also related to the reduced gastric wall compliance.     

The implication of hyperglucagonemia and -insulinemia in liver cirrhotics

Glucagon and insulin metabolism was studied in 9 cirrhotic patients and 4 non-cirrhotic controls. Net output of glucagon and insulin into portal circulation was calculated from difference between portal venous and systemic arterial concentrations multiplied by portal plasma flow. Metabolic clearance rate was also calculated as the ratio of the output to systemic concentration. Portal blood flow was measured by the continuous local thermodilution method. The results were as follows: 1) Arterial glucagon concentration was elevated in liver cirrhotics compared with non-cirrhotic-controls. Glucagon output in cirrhotics was higher than in controls [46.3 +/- 11.8 vs. 13.2 +/- 2.5 ng/min (mean +/- SEM), p less than 0.05]. Metabolic clearance rate of glucagon was not significantly different between the two groups. 2) There was a significant correlation between glucagon output and portal venous concentration of norepinephrine (r = 0.625, p less than 0.05). 3) Insulin levels in systemic arterial blood were higher in cirrhotic patients than non-cirrhotic subjects. Insulin output was not significantly different between the two groups, however, metabolic clearance rate of insulin in cirrhotics was reduced in comparison with the controls (274.5 +/- 44.3 vs. 557.7 +/- 108.6 ml/min, p less than 0.05).     

Gastric mucus generation in cirrhotic patients with portal hypertension

We have evaluated gastric mucus generation (study 1) and the effects of tetraprenylacetone on gastric mucus generation (study 2) in cirrhotic patients with portal hypertension. Study 1: Included were 50 noncirrhotics (group A), 25 cirrhotics without portal hypertension (group B), and 25 cirrhotics with portal hypertension (group C). The antrum, corpus, and fundus mucus generation was assessed by hexosamine concentration using biopsy specimens. In groups A and B, the antrum hexosamine concentration was significantly higher compared with the corpus (P<0.01,P<0.01) and the fundus (P<0.01,P<0.01). In contrast, the hexosamine concentration at each location was similar in group C. Furthermore, the antrum hexosamine concentration of group C was significantly lower compared with that of group A (P<0.05). In study 2, a double-blind design, 300 mg of tetraprenylacetone was administered for four weeks in 10 cirrhotics with portal hypertension and placebo in 10. The regional hexosamine concentrations were measured before and after drug administration. Placebo administration did not change hexosamine concentration at each location. In contrast, tetraprenylacetone increased the antrum and corpus hexosamine concentration (P<0.01,P<0.05), although the fundus concentration did not change. These data suggest that cirrhotics with portal hypertension have reduced gastric antral mucus generation and tetraprenylacetone normalizes this.     

Gastric cytoprotection by tetraprenylacetone in human subjects

We assessed the inhibition by tetraprenylacetone (TPA) of gastric mucosal damage caused by ethanol in human subjects. Seventeen healthy volunteers were given either TPA (a 50-mg capsule) or a placebo 3 times daily for 5 days. Then, 20 ml of 70% ethanol were sprayed onto the gastric antrum and 15 min later, visible mucosal lesions were evaluated with an endoscope, and biopsy specimens were taken from mucosa that looked normal but had been sprayed with ethanol. The specimens were observed by light microscopy and scanning electron microscopy. The gross mucosal damage was significantly less (p less than 0.05) in the subjects given TPA than in those given the placebo. Hyperemia and hemorrhage in the mucosa and surface epithelial damage were also significantly less (p less than 0.05) in the subjects given TPA. The results suggested that TPA protects the gastric mucosa from damage by ethanol as judged not only by the gross appearance of the mucosa but also by microscopic observation.     

Elevated plasma ammonia level in hepatic cirrhosis: role of glucagon

Elevated plasma ammonia level in hepatic cirrhosis has been attributed to a lack of conversion of enteric ammonia into urea or to its entry into systemic circulation via portasystemic shunting, or to both. It is exaggerated by excessive protein intake. Because hyperglucagonemia is well documented in cirrhosis and a protein meal is an effective glucagon secretagogue, plasma glucose, insulin, glucagon, and ammonia levels were determined in 50 cirrhotic patients after an overnight fast. Effects of a protein meal were also assessed in 20 of these patients. Plasma glucose was normal and remained unaltered after a protein meal. Insulin, glucagon, and ammonia levels were elevated, but only in patients with advanced liver dysfunction. Ammonia levels correlated significantly with glucagon (r = 0.61, p less than 0.001), but not with insulin or glucose levels. Insulin and glucagon levels rose after a protein meal in all patients and controls; whereas a significant rise in the ammonia level occurred only in decompensated cirrhotics. Elevation of the ammonia level was significantly correlated with fasting glucagon (r = 0.54, p less than 0.05), as well as with glucagon response (r = 0.65, p less than 0.01), but not with basal insulin or insulin response. Furthermore, the rise in ammonia level occurred too early to be accounted for by enteric generation. Finally, direct effects of glucagon administration on plasma glucose and serum ammonia were examined in 15 cirrhotic patients. Glucose response was significantly blunted in cirrhotic patients as compared with normal subjects, whereas serum ammonia rose promptly but only in cirrhotics, with maximum rise being noted in cirrhotic patients with advanced liver dysfunction. This study, therefore, suggests that hyperglucagonemia may contribute significantly to hyperammonemia in hepatic cirrhosis.     

Hyperglucagonemia in cirrhosis: altered secretion and sensitivity to glucagon

Plasma glucagon concentration was elevated 2- to 6-fold in cirrhotic patients with spontaneous portal systemic shunting or surgically induced portacaval anastomosis but was comparable to controls in cirrhotics without portal-systemic shunting. The metabolic clearance rate of glucagon (mol wt 3500) was normal in all of the cirrhotic groups, but the estimated basal systemic delivery rate of glucagon was increased 2- to 6-fold in the hyperglucagonemic patients. The blood glucose response to infusion of glucagon (3 ng per kg per min) was reduced in the cirrhotics with portal-systemic shunting or portacaval anastomosis, and correlated inversely with the delivery rate of endogenous glucagon. Administration of ammonium chloride (3 g) failed to elevate plasma glucagon concentration. It is concluded that hyperglucagonemia in cirrhosis is a consequence of hypersecretion rather than decreased hormonal catabolism. A negative feedback signal may exist between hepatic sensitivity to glucagon and the secretion of this hormone.     

Circulating somatostatin concentrations in healthy and cirrhotic subjects

Plasma insulin, glucagon, somatostatin, and glucose concentrations were measured in the fasting state as well as after mixed meals (breakfast, lunch, and dinner) in 10 cirrhotic patients and 10 control subjects during a 24-hour period. Cirrhotic patients had fasting glucose values higher than controls (at -15 min: 5.2 +/- 0.2 mmol/L v 3.9 +/- 0.5 mmol/L, P less than 0.05; at 0 min: 5.5 +/- 0.3 mmol/L v 4.3 +/- 0.5 mmol/L, P less than 0.01). After meals blood glucose values remained higher in cirrhotics than in controls. Insulin levels did not differ between the groups in the fasting state, but cirrhotics showed a lower response to meals. Corresponding glucagon concentrations were greater in cirrhotics than in controls before and after meals throughout the 24-hour period (from -15 min to 24 hour: P less than 0.01). BAsal plasma somatostatin levels in the cirrhotic group were significantly higher than in control subjects (at -15 min and at 0 min: P less than 0.05) and further increased after meals. Plasma somatostatin was heterogeneous in normal and cirrhotic group, but the increase in its concentrations in patients with chronic liver disease was for the most part a consequence of elevations in the 1600 and 3500 molecular weight components. The half-life of exogenously infused somatostatin in cirrhotics was comparable to that of controls. These results indicate that in liver cirrhosis elevated levels of circulating somatostatin are associated with hyperglucagonemia and impaired insulin release. The high plasma somatostatin levels observed in cirrhotic patients are the result of hypersecretion of the D cell rather than impaired removal of the peptide.