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PubMed1975

Portacaval anastomosis and peptic ulcer: a nonassociation.

The incidence of peptic ulcer is increased in cirrhosis and is widely believed to be even greater in cirrhotic patients with portacaval anastomosis (PCA). Two prospective, controlled investigations of prophylactic PCA were evaluated to compare the frequency of peptic ulcer in two groups of cirrhotic patients with similar clinical and laboratory manifestations of cirrhosis randomly selected to be an unoperated Control Group (60 patients) or to have PCA (Shunt Group, 48 patients). In addition, nonrandomized groups of cirrhotic patients, 77 of whom were excluded from the randomized study and 44 of whom had therapeutic PCA, were studied. A diagnosis of chronic peptic ulcer was based on the demonstration of an ulcer crater by X-ray, endoscopy, surgery, or autopsy. Prior to inclusion in these studies, approximately 10% of patients had had peptic ulcer. After inclusion, during a mean follow-up period of 45 months, 12% of both the Control and Shunt Groups developed peptic ulcers. The frequency of complications of peptic ulcer, of recurrence of peptic ulcer, or of acute or symptomatic (unproved) ulcer were similar in both groups. Ulcers tended to develop later in shunted than in unshunted patients. Similar data were obtained from three of four other controlled investigations of PCA. This investigation does not find an increased occurrence of peptic ulcer after PCA. The frequency of ulcer in cirrhosis appears to increase with the duration of the disease independent of the presence or absence of PCA.

Autopsy↗
PubMed1996

Portacaval anastomosis results in altered neuron--astrocytic metabolic trafficking of amino acids: evidence from 13C-NMR studies.

13C-NMR spectroscopy was used to evaluate the dynamic consequences of portacaval anastomosis on neuronal and astrocytic metabolism and metabolic trafficking between neurons and astrocytes. Glutamate is predominantly labeled from [1-13C]glucose, whereas [2-13C]acetate is more efficient in labeling glutamine, in accordance with its primary metabolism in astrocytes. Alanine and succinate labeling was only observed with [1-13C]glucose as precursor. Brain [1-13C]glucose metabolism in portacaval-shunted rats was similar to that in sham-operated controls with the exception of labeled glutamine and succinate formation, which was increased in shunted rats. The 13C enrichment was, however, decreased owing to an increase in total glutamine and succinate. Using [2-13C]acetate, on the other hand, flux of astrocytic label to neurons was severely decreased because label incorporation into glutamate, aspartate, and GABA was decreased following portacaval shunting. The latter amino acids are predominantly localized in neurons. These findings demonstrate that metabolic trafficking of amino acids from astrocytes to neurons is impaired in portacaval-shunted rats.

Acetates↗
PubMed2001

Increased density of brain histamine H(1) receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy.

The binding properties and the regional densities of histamine H(1) receptors were studied in brain of rats with portacaval anastomosis (PCA) and in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE). Receptor binding studies and quantitative receptor autoradiography were performed, employing [(3)H]mepyramine. Histamine H(1) receptors in rat brain displayed a higher density and a lower affinity compared with control human frontal cortex. Specific [(3)H]mepyramine binding was heterogeneously distributed throughout the brain in both species. In human brain, binding was highest in the parietal and temporal cortices and lowest in caudate-putamen. In rat brain, binding was highest in the suprachiasmatic nucleus, dentate gyrus of the hippocampus, ventromedial hypothalamus, and nucleus accumbens. Cortical tissue from PCA rats and frontal cortical tissue from HE patients contained significantly increased densities (B(max)) of H(1) receptors. A selective increase in H(1) receptor density was also observed in parietal and insular cortices of HE patients. Results of the present study suggest a selective up-regulation of brain H(1) receptors in PCA rats and in patients with HE. The central histaminergic system is implicated in the control of arousal and circadian rhythmicity. Previous studies have shown that blockade of H(1) receptors in PCA rats results in improved locomotor activity and circadian rhythmicity scores. The present findings suggest that cortical histaminergic hyperactivity could contribute to the neuropsychiatric symptoms characteristic of human HE, and that selective histamine H(1) receptor antagonists could be beneficial in the prevention and treatment of some of the symptoms of HE in cirrhotic patients.

Aged↗
PubMed1976

[Effects of endotoxinemia on renal and intrarenal hemodynamics of rats with or without portacaval anastomosis].

Renal dysfunction in patients with cirrhosis of the liver is frequent especially in connection with endotoxaemia. Renal and intrarenal haemodynamics were investigated, therefore, in normal rats with or without portacaval anastomosis (PCA) by means of the cardiac output (CO) fractionation technique using microspheres. The intrarenal blood distribution was estimated after anatomical separation of renal cortex and medulla. In normal rats the total renal fraction of CO was 22.5 +/- 7.2%, and the renal medulla fraction 0.8 +/- 0.4% of CO. After a single injection of E. coli-endotoxin (1.5 mg/kg b.w.) the animals developed a high-cardiac-output state, the mean arterial pressure decreased from 110 +/- 15 mm Hg to 81 +/- 6 mm Hg. Renal fraction of CO was unaltered but the blood flow through the kidney was increased due to the high CO. The blood flow of the medulla increased five to tenfold of control values whereas renal cortical blood flow decreased. During the first eight hours after endotoxin administration the animals developed polyuria with a decrease of urine osmolality. Comparable systemic and renal haemodynamics were present in untreated PCA-rats, in which endotoxaemia was present spontaneously (Limulus Gelation Test). Additional endotoxin administration in these animals caused severe shock syndrome with a decrease in total renal perfusion and a further decrease in renal cortical blood flow. Endotoxin administration in normal rats caused minimal morphological alterations in the kidneys which were comparable with those found in PCA-rats. Endotoxin administration in PCA-rats however leads to severe damage of the kidney with fibrin deposits in the glomerula and acute tubular necroses. The haemodynamic, functional and morphological changes caused by endotoxin in the experiments are observed in principle in patients with cirrhosis of the liver too. This indicates that endotoxin should be taken into considerations concerning the pathogenesis of renal failure in patients with cirrhosis of the liver.

Animals↗
PubMed1986

Effect of portacaval anastomosis on rat lipoproteins.

The distribution of cholesterol (C), triglycerides (TG), phospholipids (PL) and protein in the different lipoproteins was studied in male Wistar rats under 2 conditions: control and 2 months after portacaval anastomosis (PCA). PCA decreased the levels of cholesterol and the other components in chylomicrons (-90%), very low density lipoproteins (-65 to -78%), LDL2 (1.040 less than d less than 1.063 g/ml; -51 to -61%) and HDL (1.063 less than d less than 1.21 g/ml), whereas no change was observed in LDL1 (1.006 less than d less than 1.040 g/ml). Apoprotein C contents were decreased in all lipoproteins. The relative proportions of C, TG, PL and proteins in lipoproteins were essentially unchanged by the shunt, suggesting a reduced number of lipoprotein particles in plasma after PCA. It was concluded that PCA reduced the levels of all lipoproteins secreted by liver and/or the intestine without modifying those of intraplasmatic origin (LDL1).

Animals↗
PubMed1995

Regional alterations of dopamine and its metabolites in rat brain following portacaval anastomosis.

Hyperammonemia and changes in brain monoamine metabolism have been proposed to contribute to the pathogenesis of the neuropsychiatric symptoms characteristic of human portal-systemic encephalopathy (PSE) resulting from chronic liver disease. Portacaval anastomosis (PCA) in the rat leads to sustained hyperammonemia and mild encephalopathy. In order to evaluate the role of dopamine (DA) metabolism in PSE, levels of DA and its metabolites were measured by HPLC with electrochemical detection in brain regions of rats with PCA at various stages of encephalopathy precipitated by ammonium acetate administration. Following ammonium acetate administration, rats with PCA rapidly develop severe neurological signs of encephalopathy progressing through loss of righting reflex to coma; sham-operated control animals administered ammonium acetate showed no such neurological deterioration. Concentrations of the DA metabolites DOPAC and HVA as well as [DA metabolites]/[DA] ratios, an indirect measure of DA turnover in brain, were increased in caudate-putamen, in cingulate and pyriform entorhinal cortices as well as in raphe nucleus and locus coeruleus. Increased DA metabolites, however, did not worsen at coma stages of PSE. Increased DA turnover thus appears to relate to early neuropsychiatric and extrapyramidal symptoms of PSE.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Normalization of abnormal electroencephalograms in beagles with portacaval anastomosis by infusion of solutions rich in branched-chain amino acids.

The effects of intravenous infusions of amino acid solutions on the electroencephalograms (EEG) and biochemical indices of 12 beagle dogs with a portacaval anastomosis (PCA) were studied in unanesthetized and unrestrained conditions. EEGs were recorded everyday from 2 days after the operation. When the EEGs showed predominant delta and theta frequency bands (slow-wave), solutions of amino acids were infused intravenously at 5 ml/kg/hr for an hour. Blood was withdrawn immediately before and after the infusion to determine plasma amino acids and ammonia. Infusion of amino acid solutions enriched in branched-chain amino acids (BCAA) with restricted aromatic amino acids (AAA) normalized the predominantly slow-wave EEGs. These solutions reduced the increased plasma AAA and ammonia concentrations and increased the lowered plasma BCAA concentrations. The abnormal EEGs were not improved by infusion with a balanced and AAA-enriched amino acid solution for nutritional support of surgical patients and became worse on infusion of AAA solution. Significant correlations were found between percent changes in the incidence of slow-waves and plasma AAA concentrations. These results suggest that infusion of solution with low AAA and high BCAA concentrations may be suitable for treatment of cirrhotic patients with abnormal EEG or with hepatic encephalopathy.

Amino Acids↗
PubMed1999

Hypothalamic histamine, growth rate, plasma prolactin and growth hormone levels in rats with long-term portacaval anastomosis.

OBJECTIVE AND DESIGN: Histamine can modulate feeding behaviour and hormone release; therefore we examined the hypothalamic histamine system, the growth pattern and the serum levels of prolactin and growth hormone in rats with portacaval anastomosis (PCA). MATERIAL: The growth rate of 30 PCA- and 30 sham-operated male Han:Wistar rats was monitored for 6 months. Thirteen sham and 9 PCA rats were used for biochemical studies. METHODS: Histamine was assayed by HPLC, tele-methylhistamine by GC-MS, prolactin and growth hormone by RIA. Student's t-test was used to compare the groups. RESULTS: Six months after surgery, the PCA rats exhibited marked growth retardation (weight gain of 20 g vs. 140 g for the sham rats; p < 0.001), increased plasma levels of prolactin (9.7 +/- 2.4 vs. 3.6 +/- 0.6; p<0.01) and unaltered growth hormone levels (6.2 +/- 0.5 vs. 8.1 +/- 1.0). A six-fold elevation of histamine concentration (29.5 +/- 3.9 vs. 4.8 +/- 0.4; p<0.001) and a two-fold increase of tele-methylhistamine levels (1.8 +/- 0.1 vs. 0.8 +/- 0.02; p<0.001) were found in hypothalamus. CONCLUSION: We suggest that increased histaminergic activity in the hypothalamus may be involved in the development of growth retardation and in the enhanced basal secretion of prolactin in male rats with long-term PCA.

Animals↗
PubMed1994

Densities of binding sites for the "peripheral-type" benzodiazepine receptor ligand 3H-PK11195 are increased in brain 24 hours following portacaval anastomosis.

Quantitative receptor autoradiography was used to measure the densities of binding sites for the "peripheral-type" benzodiazepine receptor ligand 3H-PK11195 in regions of the rat brain 1, 3, 7 and 28 days following portacaval anastomosis (PCA) and in sham-operated control animals. The results demonstrate that densities of 3H-PK11195 binding sites were significantly increased in the cerebral cortex (by 40%, p < 0.05) as early as 24 hours following PCA. In the thalamus significant increases in densities of 3H-PK11195 binding sites were seen 3 days after PCA, whereas in brain regions such as the striatum and cerebellum, significant increases in 3H-PK11195 binding sites were not evident until 7 days following PCA. By 28 days following PCA increased densities of 3H-PK11195 binding sites were well established and widespread throughout the brain. Previous studies demonstrate early increases of brain ammonia following PCA. PTBRs or their endogenous ligands could play an important role in the early astrocytic response (mitochondrial proliferation, swelling) to ammonia following PCA.

Animals↗
PubMed1987

Effect of portacaval anastomosis on plasma lipoproteins of lean and obese Zucker rats.

The distribution of cholesterol (C), triglycerides (TG), phospholipids (PL) and proteins in the different lipoproteins was studied in lean and obese Zucker rats under 2 conditions: non-operated and after portacaval anastomosis (PCA). All lipoproteins, but mainly the d less than 1.006 g/ml (chylomicrons + VLDL) fraction, were increased in obese rats. They were hypertriglyceridemic (+ 675%) and hypercholesterolemic (+ 207%). PCA decreased cholesterolemia by about 50% and triglyceridemia by 50-70% in both lean and obese rats. Except for VLDL, enriched in TG in obese rats, proportions of C, TG, PL and proteins in lipoproteins were about the same in obese and lean Zucker rats and were nearly unchanged by PCA, suggesting an increased number of particles in obese rats and a decreased number after PCA. Lipoproteins of obese rats were enriched in apo C and proportions of apo E and apo B were decreased in the d less than 1.006 g/ml fraction. PCA decreased the proportion of apo C in all lipoproteins.

Animals↗
PubMed1980

Pituitary and thyroid function before and after portacaval anastomosis in patients with normal livers.

Basal plasma thyroid hormone, testosterone and cortisol levels, TSH and PRL responses to TRH, and LH and FSH responses to LRH were assessed in six young subjects with normal liver function and anatomy before and after portacaval anastomosis. All tests were normal and unchanged by the operations. It is concluded that in patients with normal liver function, portal systemic shunting does not produce alterations in the pituitary-gonadal and pituitary-thyroid axes. The abnormalities of these endocrine functions in patients with cirrhosis are probably related to the severity of hepatocellular dysfunction rather than to the effects of portal systemic shunting.

Adolescent↗
PubMed2000

Effects of the histamine H(1) receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis.

To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portal-systemic encephalopathy, we examined the effects of histamine H(1) receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H(1) receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H(1) receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [(3)H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H(1) receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H(1) receptors in both sham- and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H(1) receptor-mediated mechanism.

Animals↗
PubMed1997

Stenosis of a portacaval anastomosis affects circadian locomotor activity in the rat: a multivariable analysis.

The study of hepatic encephalopathy is limited by the lack of standardized experimental models to assess behavior. We have shown that rats continuously monitored while running on a wheel show abnormalities of the circadian rhythm of locomotor activity after portacaval anastomosis (PCA), such that entrainment of running activity to the light-dark cycle is severely impaired. To identify factors that affect postoperative circadian behavior, we have performed a multivariable analysis of 69 sham-operated controls and 107 rats after PCA. Our results indicate that shunt stenosis, as determined by the pressure gradient from the splenic pulp to the inferior vena cava, ameliorated the postoperative deterioration of the circadian rhythm. In addition, postoperative behavior was affected by preoperative performance, diet, and gender. Postoperative body weight gain, spleen weight, and liver atrophy did not impact this model. Because shunt stenosis is known to ameliorate hepatic encephalopathy in humans, our findings support the validity of this behavioral end point as a correlate of hepatic encephalopathy. Measurement of the pressure gradient across the anastomosis and achievement of sufficient preoperative entrainment appear critical for the standardization of the model.

Animals↗
PubMed2005

Neuronal and inducible nitric oxide synthase expression in the rat cerebellum following portacaval anastomosis.

In order to determine the role of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in the pathogenesis of experimental hepatic encephalopathy (HE), the expression of both was analyzed in the cerebellum of rats 1 month and 6 months after performing portacaval anastomosis (PCA). In control cerebella, nNOS immunoreactivity was mainly observed in the molecular layer (ML), whereas the Purkinje cells did not express nNOS. However, nNOS expression was detected in the Purkinje cells at 1 month after PCA, correlating with a decrease in nNOS expression in the ML--part of an overall reduction in cerebellar nNOS concentrations (as determined by Western blotting). At 6 months post-PCA, a significant increase in nNOS expression was observed in the ML, as well as increased nNOS immunoreactivity in the Purkinje cells. nNOS immunoreactivity was also observed in the Bergmann glial cells of PCA-treated rats. While no immunoreactivity for iNOS was seen in the cerebella of control rats, iNOS immunoreactivity was significantly induced in the cerebellum 1 month after PCA. In addition, the expression of iNOS was greater at 6 months than at 1 month post-PCA. Immunohistochemical analysis revealed this iNOS to be localized in the Purkinje cells and Bergmann glial cells. The induction of iNOS in astroglial cells has been associated with pathological conditions. Therefore, the iNOS expression observed in the Bergmann glial cells might play a role in the pathogenesis of HE, the harmful effects of PCA being caused by them via the production of excess nitric oxide. These results show that nNOS and iNOS are produced in the Purkinje cells and Bergmann glial cells following PCA, implicating nitric oxide in the pathology of HE.

Animals↗
PubMed1983

Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.

Measurements of the key parameters of cholesterol homeostasis and the mass of the body pools of cholesterol were carried out in two patients with familial hypercholesterolemia (FH), one homozygote and one heterozygote, before and 28 and 18 months, respectively, after portacaval anastomosis (PCA). In both patients the procedure significantly reduced the plasma concentrations of total and low density lipoprotein cholesterol and the daily rate of whole body cholesterol and bile acid synthesis. In addition, PCA caused a net efflux of accumulated tissue cholesterol as demonstrated by reductions in the rapidly exchangeable and total exchangeable masses of body cholesterol. Shunt patency was verified by demonstration of increased bile acids in serum from fasting patients and from patients 2 hr after a meal and by increased plasma glucagon before and after arginine infusion. Other than a persistently increased level of serum alkaline phosphatase, liver function tests have fallen within the normal range in both patients; there has been no evidence of hepatic encephalopathy. In the homozygous patient there has also been a striking resolution in xanthoma size and distribution. These multiple effects on cholesterol homeostasis and pool sizes strongly suggest that PCA can reverse the progressive accumulation of cholesterol in body tissues of FH patients.

Bile Acids and Salts↗
PubMedDate not supplied

Increased brain content of the endogenous benzodiazepine receptor ligand, octadecaneuropeptide (ODN), following portacaval anastomosis in the rat.

Evidence suggests that endogenous benzodiazepine receptor ligands such as diazepam binding inhibitor (DBI) and its metabolite octadecaneuropeptide (ODN) may be implicated in the pathogenesis of hepatic encephalopathy. Using an immunocytochemical technique and an antibody of high specific activity to synthetic ODN, we studied the effects of portacaval anastomosis (PCA) on ODN distribution in rat brain. Four weeks after PCA, ODN immunolabeling was increased in several brain regions including cerebral cortex, hippocampus, hypothalamus and thalamus. Increased ODN immunolabeling was confined to nonneuronal elements such as astrocytes and ependymal cells. Neuropathological evaluation of brain following PCA reveals astrocytic rather than neuronal changes. These results are consistent with a role for endogenous neuropeptide ligands for astrocytic benzodiazepine receptors in the pathogenesis of hepatic encephalopathy.

Animals↗