Choline acetyltransferase and acetylcholinesterase activities are unchanged in brain in human and experimental portal-systemic encephalopathy

Activities of choline acetyltransferase, acetylcholinesterase and butyrylcholinesterase were studied in the frontal cortex, temporal cortex, cerebellum and caudate nucleus obtained at autopsy from eight alcoholic cirrhotic patients who died in hepatic coma and from an equal number of age-matched subjects free from hepatic, neurological or psychiatric disorders. Activities of these enzymes were unaltered in the brains of cirrhotics compared to controls. Choline acetyltransferase and cholinesterase activities were also studied in the cerebral cortex, cerebellum, brain stem and striatum of rats four weeks following portacaval anastomosis and their sham-operated controls. Portacaval-shunting did not cause any statistically significant differences in the activities of choline acetyltransferase, acetyl or butyrylcholinesterases. These results argue against a presynaptic cholinergic lesion in human and experimental portal-systemic encephalopathy.     

Hemodynamic effects of blood volume restitution following a hemorrhage in rats with portal hypertension due to cirrhosis of the liver: influence of the extent of portal-systemic shunting

The present study investigated whether, in rats with portal hypertension due to cirrhosis of the liver induced by carbon tetrachloride, blood volume restitution following a hemorrhage produces an increase of portal pressure beyond control values, as observed in rats with prehepatic portal hypertension. Since carbon tetrachloride-induced cirrhosis caused mild portal-systemic shunting, in some of the cirrhotic rats (12 of 29 rats) portal-systemic shunting was enhanced by a transient (4 days) partial constriction of the portal vein, which was removed 1 week prior to the study. After baseline measurements of portal pressure and arterial pressure, 15 ml per kg of blood were withdrawn at a rate of 0.3 ml per min and reinfused 15 min later. After blood reinfusion, portal pressure and arterial pressure were measured again, and cardiac output, regional blood flows and portal-systemic shunting were determined using radioactive microspheres. Portal-systemic shunting was 78 +/- 11% of total blood flow in the cirrhotic rats that had temporary portal vein constriction, but only 5 +/- 2% (p less than 0.001) in those that did not. Blood volume restitution in low-portal-systemic shunting rats did not produce any significant modification in splanchnic or systemic hemodynamics. However, in rats with high portal-systemic shunting, blood volume restitution produced a significant increase in portal pressure (from 9.9 +/- 0.9 to 13.5 +/- 0.9 mmHg, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Aromatic and branched-chain amino acids in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

Concentrations of the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine and the aromatic amino acids (AAAs) phenylalanine and tyrosine were measured in three areas of dissected brain tissue obtained at autopsy from nine cirrhotic patients who died in hepatic encephalopathy. The controls were an equal number of subjects free from neurological, psychiatric or hepatic diseases, matched for age and time interval from death to freezing of autopsied brain samples. Amino acids were measured using high-performance liquid chromatography with fluorimetric detection. In brain tissue of cirrhotic patients, no changes in BCAA concentrations were observed compared with controls. On the other hand, phenylalanine levels were found to be increased 141% in prefrontal cortex, 86% in frontal cortex and 26% in caudate nucleus, and tyrosine content was increased by 71% in prefrontal cortex and 28% in frontal cortex with no significant increase in caudate nucleus. Alterations in the concentration of AAAs may lead to disturbances of monoamine neurotransmitters in brain. Such changes could play a role in the pathogenesis of hepatic encephalopathy resulting from chronic liver disease in man.     

The effect of portal-systemic shunting on hepatic sex hormone receptors in male rats

Signs of feminization are seen in men with cirrhosis of alcoholic but also of nonalcoholic origin even in the absence of markedly increased plasma estrogen levels. Recently identified alterations of hepatic sex hormone receptor levels have provided a hypothetical mechanism for the pathogenesis of the feminization seen in cirrhotic men. The aim of the present study was to determine the effect of experimental portal-systemic shunting in adult male rats on hepatic sex hormone receptor levels, plasma sex hormones, and two markers for sex hormone action in the liver. The following alterations were found in male rats with surgically created portacaval shunts compared with sham-operated controls: the hepatic content of cytosolic estrogen receptors was reduced by 35% and the cytosolic androgen receptors content by 59%; plasma levels of estradiol increased 6.7-fold while those of testosterone were reduced by 71%; the estrogen-responsive ceruloplasmin levels were decreased by 31% and the androgen-responsive male-specific estrogen binder by 72%. Based on these data, it can be concluded that portal-systemic shunting reduces the hepatic cytoplasmic content of several sex hormone related proteins. These changes are paralleled by a decreased estrogen responsiveness of the liver, as evidenced by the plasma ceruloplasmin level.     

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.     

Portacaval Anastomosis Results in More Widespread Alterations of Cerebral Metabolism in Old Versus Young Adult Rats: Implications for Post-Shunt Encephalopathy

Treatment of portal hypertension by portal decompressive surgery or transjugular intrahepatic portosystemic stent shunt (TIPS) results in new or worsening episodes of portal-systemic encephalopathy, particularly in older patients. As part of a series of studies to elucidate the pathophysiologic mechanisms responsible for the age-related increased portal-systemic encephalopathy following shunt surgery, local cerebral glucose utilization, a measure of regional brain functional activity, was assessed using the ¹⁴C-2-deoxyglucose autoradiographic technique in 2 month-old (young adult) and 24 month-old (old adult) rats following end-to-side portacaval anastomosis. Cerebral glucose utilization was decreased by 22% (p<0.05) in frontal cortex of 2 month-old rats following portacaval anastomosis. More widespread alterations of glucose utilization, involving frontal and frontoparietal cortices, as well as thalamic structures were observed in the brains of 24 month-old rats following portacaval anastomosis despite blood ammonia concentrations of a comparable magnitude. Decreased cerebral glucose utilization in frontal and frontoparietal cortex of old adult rats following portacaval anastomosis probably results from decreased cerebral energy requirements as a consequence of neurotransmitter-related dysfunction. The greater susceptibility of aging brain to the deleterious effects of portacaval anastomosis is consistent with the higher incidence of encephalopathy in older cirrhotic patients following portacaval anastomosis or TIPS.     

Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging

Changes are shown in the spin-lattice (T1) relaxation time caused by the putative deposition of manganese in various brain regions of hepatic encephalopathy (HE) patients using a novel and fast magnetic resonance imaging (MRI) method for quantitative relaxation time mapping. A new method, T1 mapping with partial inversion recovery (TAPIR), was used to obtain a series of T1-weighted images to produce T1 maps. Imaging of 15 control subjects and 11 patients was performed on a 1.5T MRI scanner. The measurement time per patient with this technique, including adjustments, was approximately 5 minutes. Regions of interest in the globus pallidus, the caudate nucleus, the posterior and anterior limbs of the internal capsule, the putamen, the frontal and occipital white matter, the white matter of the corona radiata, the occipital visual and frontal cortices, and the thalamus were interactively defined in the left hemisphere and analyzed with respect to their T1 values. T1 changes in the brains of HE patients can be determined quantitatively with TAPIR in short, clinically relevant measurement times. Significant correlations between the change in T1 and HE severity have been shown in the globus pallidus, the caudate nucleus, and the posterior limb of the internal capsule. No significant correlation of T1 with grade of HE was found in the putamen, frontal white matter, white matter of the corona radiata, white matter in the occipital lobe, the anterior limb of the internal capsule, visual cortex, thalamus, or frontal cortex. In conclusion, these measurements show that T1 mapping is feasible in short, clinically relevant acquisition times.     

Increased blood flow through the portal system in cirrhotic rats

Portal venous pressure is the result of the interplay between portal venous blood flow and the vascular resistance offered to that flow. Whether portal hypertension is maintained only by an increased portal venous resistance or also by an increased blood flow within the portal venous system is still open to speculation. To resolve these differences, splanchnic and systemic hemodynamics were evaluated in cirrhotic rats, induced by CCl4. Blood flow and portal-systemic shunting were measured by radioactive microsphere techniques. All cirrhotic rats had portal hypertension (portal venous pressure 13.5 +/- 1.1 vs. 9.0 +/- 0.5 mmHg, in normal control rats; p less than 0.01), but portal-systemic shunting in cirrhosis (31% +/- 13% vs. 0.2% +/- 0.02%; p less than 0.05) was variable, ranging from 1% to 97%. Portal venous inflow, the total blood flow within the portal system, was increased in cirrhotic rats (5.75 +/- 0.04 vs. 4.52 +/- 0.36 ml/min per 100 g; p less than 0.05). Total splanchnic arterial resistance was reduced in cirrhotic rats (3.3 +/- 0.2 vs. 5.8 +/- 0.5 dyn X s X cm-5 X 10(5); p less than 0.01). Portal venous resistance, however, was not abnormally elevated in cirrhotic rats (4.6 +/- 0.5 vs. 4.7 +/- 0.5 dyn X s X cm-5 X 10(4), p = NS). Splanchnic hemodynamics in cirrhotic rats demonstrate that portal hypertension is maintained, at least in part, by a hyperdynamic portal venous inflow. The hemodynamic data in cirrhotic rats provided evidence that supports the role of an increased portal blood flow in portal hypertension and gives a quantitative definition of splanchnic hemodynamics in intrahepatic portal hypertension.     

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.     

Effects of spontaneous portal-systemic shunting on insulin metabolism.

Insulin degradation was measured by the C-peptide/insulin ratio in 19 patients with portal vein block with extensive spontaneous portal-systemic shunting but minimal liver cell damage: 13 patients with biopsy-proved cirrhosis and 12 controls. Blood obtained fasting and for 3 hr after oral glucose was assayed for glucose, insulin, and C-peptide. Fasting C-peptide and insulin levels in patients with portal vein block and those in controls did not differ. Eight of 13 cirrhotic patients had fasting hyperinsulinemia with a significantly reduced C-peptide/insulin ratio. After glucose administration, the C-peptide/insulin ratio in portal vein block patients with normal aspartate transaminase levels did not differ from control values. In portal vein block patients with elevated asparatate transaminase levels, the C-peptide/insulin ratio was significantly reduced only from 60 min onwards. All the cirrhotic patients showed a significantly reduced C-peptide/insulin ratio after glucose administration. It is suggested that portal-systemic shunting of blood in the presence of a normal liver does not influence hepatic insulin metabolism and that the hyperinsulinemia of cirrhosis is a feature of parenchymal liver damage. In addition, insulin degradation was abnormal in all cirrhotic patients at high insulin secretion rates, even when fasting insulin levels were normal.     

Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy

Peripheral-type benzodiazepine receptors were evaluated using the specific ligand [3H]-PK 11195 in brain homogenates from nine cirrhotic patients who died in hepatic coma and from an equal number of age-matched control subjects. Histopathological studies showed evidence of severe Alzheimer type II astrocytosis in the brains of all cirrhotic patients. Saturation-binding assays revealed a single saturable binding site for [3H]-PK 11195 in brain, with affinities in the 2- to 3-nmol/L range. Diazepam was found to be a relatively potent inhibitor of 3H-PK 11195 binding (IC50 = 253 nmol/L), whereas the central benzodiazepine antagonist Ro 15-1788 displaced 3H-PK 11195 binding with low affinity (IC50 greater than 40 mumols/L). Densities of [3H]-PK 11195 binding sites were found to be increased by 48% (p less than 0.01) and 25% (p less than 0.05) in frontal cortex and caudate nuclei, respectively, from cirrhotic patients. Densities of [3H]-PK 11195 binding sites in frontal cortex from two nonencephalopathic cirrhotic patients were not significantly different from control values. No concomitant changes of affinities of these binding sites were observed. Because it has been suggested that peripheral-type benzodiazepine receptors may be localized on mitochondrial membranes and may therefore be involved in cerebral oxidative metabolism, the alterations observed in this study could be of pathophysiological significance in hepatic encephalopathy.     

Regional brain monoamines and their metabolites after portacaval shunting

Disturbances in brain monoamine neurotransmitter metabolism have been implicated in the development of hepatic encephalopathy produced by portacaval shunting or liver disease. We have measured the content of serotonin, norepinephrine and dopamine, as well as their metabolites 5-hydroxyindoleacetic acid, dihydroxyphenylacetic acid and homovanillic acid in nine selected brain areas of rats with portacaval shunts and sham-operated control rats. All substances were measured in single samples using high performance liquid chromatography with electrochemical detection, after a simple extraction procedure. In shunted rats serotonin content was 26% higher in the raphe nuclei area, and 5-hydroxyindoleacetic acid throughout the brain (by 51 to 137%), suggesting increased serotonin turnover. Norepinephrine content was higher by 26% in the frontal cortex. Dopamine content was unaffected; however its metabolites were higher in a few areas including the caudate and ventral tegmentum. Brain content of the monoamine precursor amino acids tryptophan, tyrosine and phenylalanine was higher throughout the brain in the shunted rats. The results suggest that serotonin metabolism is altered throughout the brain after portacaval shunting, which could be related to some of the characteristic behavioral abnormalities found in this condition. Catecholamine metabolism appears to be more selectively and less extensively affected.     

Quantitative aspects of portal-systemic and arteriovenous shunts within the liver in cirrhosis

To estimate vascular changes in chronic liver disease, we quantitated intrahepatic arteriovenous and portal-systemic shunts in 12 patients with cirrhosis and arteriovenous shunts alone in 4 patients with cirrhosis. An index was obtained for intrahepatic arteriovenous shunts by instilling technetium 99m-macroaggregated albumin into the proper hepatic artery and portal-systemic shunts, by the same procedure done in the portal trunk, near the porta hepatis on different days. Counts were taken over the liver and both lungs in the anterior as well as the posterior view for calculation of the shunt index: cpm in lungs divided by cpm in liver and lungs X 100%. In the 12 patients with cirrhosis in whom both shunts were measured, intrahepatic arteriovenous shunting was significantly lower compared with intrahepatic portal-systemic shunting (1.4% +/- 1.1% vs. 36.0% +/- 29.0%, p less than 0.001). Thus, it seems that in patients with cirrhosis, the development of intrahepatic arteriovenous shunts is not as great as that of portal-systemic shunts, which were found in this study to be considerable and variable in degree.     

Morphological changes of rat astrocytes induced by liver damage but not by manganese chloride exposure

Liver cirrhosis is a common cause of death around the world. One of its more severe complications is hepatic encephalopathy. As a consequence of liver impairment, manganese (Mn) and other substances accumulate in the brain. Astrocytic morphological changes have been found in postmortem brains of cirrhotic patients. In this study we used a model of cirrhosis induced by bile duct ligation and Mn accumulation by exposing rats to MnCl₂ (1 mg Mn/ml) in their drinking water. Four experimental groups were used: Sham, Sham plus Mn treatment, BDL (bile duct ligated) and BDL plus Mn treatment. Brain Mn was measured by atomic absorption spectrophotometry in cortex, striatum and globus pallidus. Altered and normal astrocytes were counted in the same brain areas. Brain Mn was highest in rats of the BDLMn group. An increased number of altered astrocytes was found only in BDL groups, Mn did not modify this effect. No changes were found in the total number of astrocytes. According to our results, biliary obstruction induced an increase in the number of altered astrocytes since early stages of cirrhosis and Mn did not affect this effect.     

Determination of functional portal-systemic shunting in patients submitted to hepatic angiography

Abstract: Angiographic visualization of the hepatic vascular bed by selective angiography can be profitably complemented with the evaluation of functional portal-systemic shunting by D-sorbitol bioavailability. Seventeen patients requiring diagnostic arterial catheterization were studied: most of them had biopsy-proven liver cirrhosis. Patients were studied at rest and after overnight fasting on two subsequent days, in which a sterile pyrogen-free solution (1.5%) of D-sorbitol was administered by direct infusion (15 mg/min for 20 min) into the superior mesenteric artery and an antecubital vein, respectively. The fractional bioavailability (Fma) of Dsorbitol was calculated as the ratio between the net cumulative urinary outputs obtained after infusion through the catheter into the superior mesenteric artery and the systemic vein, respectively. A good correlation was found between the estimated fractional portal-systemic shunting, which in the present study ranged between 1.4% and 96.7%, and a suitable index scoring the clinical evidence of collateral circulation. Since the hepatic removal of D-sorbitol is not affected by sinusoidal capillarization and its hepatic extraction ratio is quite high and only slightly modified by reduction in the number or functional activity of hepatocytes, the measured Fma can be assumed as a parameter reflecting the entity of portal-systemic shunting. The test is safe and inexpensive, and appears potentially useful in several situations in which portal-systemic shunting is pathophysiologically relevant.     

Rat CCl4‐induced cirrhosis plus total portal vein ligation: a new model for the study of hyperammonaemia and brain oedema

Introduction: Animal models used to study hyperammonaemic disorders related to chronic liver disease are unsatisfactory. These animals only develop hyperammonaemia and brain oedema when fed with diets supplemented with amonium acetate. Aim: To develop a novel experimental model of hyperammonaemia and brain oedema in CCl₄‐induced cirrhosis in rats. Methods: Four groups were studied: rats with sham intervention (S), rats with total portal vein ligation (TPVL), cirrhotic rats (LC), and cirrhotic rats with TPVL (LC+TPVL). When ascites was diagnosed, oral glutamine challenge (OGC) test was performed. Blood, liver, lungs and brain samples were collected to quantify liver function parameters, plasmatic and cerebral ammonia, endotoxaemia, liver and brain histology, brain oedema and portosystemic shunting degree. Results: LC+TPVL rats showed a significant increase in portosystemic shunting when compared with LC group and a significant derangement in liver function when compared with TPVL group. These alterations resulted in a significant increase in plasmatic and brain ammonia concentrations and a higher plasmatic endotoxaemia as compared with others. Similarly, the area under OGC curve was significantly increased in LC+TPVL group as compared with the others, and correlates with portal shunting. Low‐grade brain oedema was only observed in LC+TPVL group. All cirrhotic groups showed liver regeneration nodules and type‐II Alzheimer astrocytes Conclusion: LC+TPVL reproduce the main alterations – portosystemic shunting, plasmatic and cerebral hyperammonaemia and low‐grade brain oedema – observed in cirrhotic patients with hepatic encephalopathy.     

Increased bioavailability of enzymes of eicosanoid synthesis in hepatic and extrahepatic tissues after portacaval shunting

Metabolites of arachidonic acid have been attributed to severe circulatory, metabolic and hormonal alterations in patients with chronic liver disease. In order to study changes of the tissue-specific availability of enzymes of eicosanoid synthesis, we used portacaval-shunted rats, as this model exhibits many clinical and biochemical similarities to patients suffering from cirrhosis of the liver. Microsomal mass and maximal velocity of prostaglandin H synthase, the initial enzyme of prostaglandin synthesis, were markedly and permanently increased after shunting in both hepatic and extrahepatic tissues as compared to those of sham-operated rats. Maximal velocity of thromboxane synthase and prostacyclin synthase, two more peripheral enzymes of the arachidonic acid cascade, were tissue-specifically enhanced, whereas the apparent affinities (Km) remained unchanged. Determination of 5-lipoxygenase activity in tissue preparations disclosed a preferential increase in the liver, lung and renal cortex after portacaval shunting. Furthermore, exposure to endotoxin closely mimicked the shunting-induced changes. These results suggest that after portacaval shunting and possibly in patients with advanced liver disease, profound abnormalities at the level of local enzyme expression might play a pathophysiologically important role in the control of eicosanoid synthesis.     

Effects of norepinephrine and acetylcholine on portal-systemic collaterals of common bile duct-ligated cirrhotic rat

BACKGROUND: Catecholamine exerts profound vascular effects on vascular smooth muscle, and serum norepinephrine (Nepi) and sympathetic nervous activity are increased in cirrhosis. The vascular response of Nepi and acetylcholine (Ach) in portal-systemic collaterals of cirrhotic rats is unknown. The purpose of the present study was to investigate the effects of Nepi and Ach on portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats. METHODS: Perfusion studies were performed 6 weeks after BDL when hepatic cirrhosis was induced. Three series of experiments were performed in BDL rats: (i) the Nepi (10(-10) mol/L-10(-5) mol/L) vasoconstrictory responses with (n = 6) and without (n = 5) alpha1- (phentolamine, 5 x 10(-6) mol/L) or beta- (propranolol, 10(-5) mol/L) receptor antagonist (n = 6 and 5, respectively); (ii) the Ach (10(-8) mol/L-10(-5) mol/L) vasodilatory responses in Nepi- preconstricted portal-systemic collaterals in the absence (n = 7) or presence (n = 8) of N(pi)- L-nitro-arginine (NNA, 10(-4) mol/L); and (iii) the effect of indomethacin (10(-5) mol/L; n = 6) on Nepi responses. The collateral vascular responses were evaluated by the in situ collateral perfusion. Results: Norepinephrine significantly increased the perfusion pressure and was inhibited by phentolamine (P < 0.05). The constrictive responses of Nepi were not significantly modified in the presence of propranolol (P > 0.05). Acetylcholine produced >50% relaxation of the Nepi-preconstricted collateral vessels and was inhibited by NNA (P < 0.05). In addition, indomethacin significantly enhanced the constrictive response of Nepi (P < 0.05). Conclusion: Norepinephrine has a vasoconstrictive effect on the portal-systemic collaterals of cirrhotic rats and this effect was mediated by alpha1-receptor. Both nitric oxide and prostaglandin are endogenous modulators in the collateral circulation of cirrhotic rats.     

Decrease of regional cerebral blood flow in liver cirrhosis

OBJECTIVE: Alterations of regional cerebral blood flow (rCBF) in subjects with liver cirrhosis have not been fully evaluated. We evaluated quantitative changes in rCBF using single photon emission computed tomography (SPECT). METHODS: Twenty-eight Japanese patients with liver cirrhosis were enrolled in this study. None of them exhibited advanced hepatic encephalopathy at the time of examination. The cause of liver cirrhosis was viral infection in 26 patients; the cause was unknown in two patients. Child-Pugh classification of the patients was as follows: Group A, 12 patients; Group B, 12 patients; and Group C, four patients. The control group consisted of 25 age-matched healthy subjects. Radionuclide angiography was performed by rapid injection of Tc-99m ethyl cysteinate dimer (ECD) (740 MBq) via the right cubital vein, and then SPECT brain images were taken. Using the Patlak graphical method, rCBF values (ml/100 g per min) were calculated in the frontal, parietal, temporal and occipital lobes and cerebellum on SPECT images. RESULTS: The rCBF values were lower in cirrhotic patients than in controls, i.e. by 15% in the frontal lobe, by 12% in the parietal lobe, by 10% in the temporal and occipital lobes, and by 7% in the cerebellum. They decreased concomitantly with the severity of liver disease. A significant negative correlation was noted between rCBF values and Child-Pugh score in the frontal (P<0.01), parietal (P<0.05) and occipital lobes (P<0.01). rCBF values of each region were not correlated with age or with results of neuropsychological test. The degree of association between rCBF values and results of laboratory examination was generally poor. CONCLUSION: Patients with liver cirrhosis without advanced encephalopathy showed widespread reduction in rCBF; this reduction was particularly evident in the frontal lobe. Tc-99m ECD SPECT may be useful for evaluating cerebral functional changes in patients with liver cirrhosis.