Near-Infrared Spectroscopy Reveals Brain Hypoxia and Cerebrovascular Dysregulation in Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease linked to symptoms including fatigue and altered mood/cognition, indicating that chronic liver inflammation associated with PBC can impact brain function. We employed near-infrared spectroscopy (NIRS), a noninvasive neuroimaging technique, to determine whether patients with PBC exhibit reduced cerebral oxygen saturation (StO2 ) and altered patterns of microvascular cerebral blood perfusion and whether these alterations were associated with clinical phenotype. This observational case-control study was conducted at a tertiary hospital clinic (University of Calgary Liver Unit). APPROACH AND RESULTS: Thirteen female patients with noncirrhotic PBC, seven female patients with cirrhotic PBC, and 11 healthy female controls were recruited by physician referral and word of mouth, respectively. NIRS was used to measure cerebral hemoglobin and oxygen saturation. A wavelet phase coherence method was used to estimate the coherent frequency coupling of temporal changes in cerebral hemodynamics. The PBC group demonstrated significantly reduced cerebral StO2 (P = 0.01, d = 0.84), indicating cerebral hypoxia, significantly increased cerebral deoxygenated hemoglobin concentration (P < 0.01, d = 0.86), and significantly reduced hemodynamic coherence in the low-frequency band (0.08-0.15 Hz) for oxygenated hemoglobin concentration (P = 0.02, d = 0.99) and total hemoglobin (tHb) concentration (P = 0.02, d = 0.50), indicating alterations in cerebrovascular activity. Complete biochemical response to ursodeoxycholic acid (UDCA) therapy in early patients with PBC was associated with increased cerebral tHb concentration and decreased hemodynamic coherence. CONCLUSIONS: Using NIRS, patients with PBC were found to have hypoxia, increased cerebral hemoglobin concentration, and altered cerebrovascular activity, which were reversed in part in UDCA responders. In addition, symptoms and quality-of-life measures did not correlate with brain hypoxia or cerebrovascular dysregulation in patients with PBC.

Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats.

The serotonin neurotransmitter system, including the 5-HT(3) receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT(3) receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT(3) receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT(3) receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT(3) receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT(3) receptor antagonism, thereby implicating the 5-HT(3) receptor system in cholestasis associated fatigue.

Suppression of hypothalamic-pituitary-adrenal axis responsiveness to stress in a rat model of acute cholestasis.

Cholestatic patients undergoing surgery have increased mortality and demonstrate clinical features suggestive of adrenal insufficiency. To examine whether cholestasis influences the status of the hypothalamic-pituitary-adrenal axis, we evaluated rats with acute cholestasis caused by bile duct resection (BDR) and sham-operated and unoperated controls. Basal unstressed plasma concentrations of ACTH and corticosterone were similar in BDR and sham-operated and unoperated control rats. However, exposure of BDR rats to saturated ether vapor resulted in significantly less ACTH and corticosterone release in plasma than in the control animals. To understand the mechanism(s) of decreased HPA axis responsiveness to ether stress in cholestasis, we administered corticotropin-releasing factor (CRF) and measured hypothalamic content, mRNA levels and in vitro secretion of CRF and arginine vasopressin (AVP), the two principal secretagogues of ACTH. In BDR animals, ACTH responses to CRF were decreased and hypothalamic content of CRF and CRF mRNA expression in the paraventricular nucleus were decreased by 25 and 37%, respectively. Furthermore, CRF release from hypothalamic explants of BDR rats was 23% less than that of controls. In contrast to CRF, hypothalamic content of AVP was 35% higher, AVP mRNA in the paraventricular nucleus was increased by 6.6-fold, and hypothalamic explant release of AVP was 24% higher in BDR rats than in control animals. Pituitary ACTH contents were similar in BDR and sham resected rats, but higher than unoperated controls. These findings demonstrate that acute cholestasis in the rat is associated with suppression of hypothalamic-pituitary-adrenal axis responsiveness to stress and demonstrate a dissociation between mechanisms of ACTH regulation mediated by CRF and AVP.

Induction versus noninduction antiviral therapy for chronic hepatitis C virus in patients with congenital coagulation disorders: a Canadian multicentre trial.

BACKGROUND: Patients with congenital coagulation disorders and chronic hepatitis C virus (HCV) infection have multiple risk factors (ie, infection predominantly with genotype-1 HCV, long duration of the disease, HIV coinfection and male sex) for poor response to antiviral therapy. The present study compared induction therapy with interferon-alpha (IFN-alpha)-2b with standard IFN-alpha2b therapy. Pegylated IFN was not available at the time that the study was initiated. PATIENTS AND METHODS: A randomized study was performed comparing the efficacy of traditional IFN-alpha2b therapy (group A -- three million units, three times weekly for 24 to 48 weeks) and daily ribavirin (1.0 g to 1.2 g according to weight for 24 to 48 weeks), with induction IFN-alpha2b therapy (group B -- three million units, daily for eight weeks followed by the same dose administered three times a week for a further 16 to 40 weeks) and daily ribavirin (same dose as above) in IFN-naive patients with congenital coagulation disorders and chronic HCV infection. RESULTS: Between 2000 and 2003, 54 HIV-negative patients were recruited and randomly assigned to group A or B (n=27 each). Both groups were comparable in terms of age, sex, ethnicity, body mass index, baseline HCV RNA titre, viral genotype, liver fibrosis stage and type of coagulation disorder. Induction therapy did not significantly alter sustained virological response rates (group A 50%, group B 50%; P=1.0). Multiple logistic regression analysis indicated that induction therapy did not benefit individuals with difficult-to-treat infection (ie, those infected with genotypes 1 and 4, or those with high baseline viral loads). CONCLUSIONS: There was no benefit with induction antiviral therapy for HCV infection in individuals with congenital coagulation disorders.

Tenofovir disoproxil fumarate significantly decreases serum lipoprotein levels compared with entecavir nucleos(t)ide analogue therapy in chronic hepatitis B carriers.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are first-line treatments for chronic hepatitis B (CHB). Studies suggest lipid lowering effect of TDF in human immunodeficiency virus positive (HIV+) individuals, but the effect on lipids and cardiovascular disease (CVD) risk in CHB is unknown. AIM: To compare TDF vs ETV effects on lipid levels in CHB. METHODS: In this retrospective cohort study, data on serum lipids and CVD risk factors at baseline and ~1 year on TDF or ETV were collected from CHB carriers. We used propensity score matched models to assess the effect on total cholesterol (TC), LDL-C, HDL and triglycerides (TGL). RESULTS: In 348 patients, median age was 57 (IQR: 47-65 years), 63% were male, 77% were Asian, 19% were cirrhotic, 25% were HBeAg positive at baseline, and 72% received TDF vs 28% ETV. ETV-treated patients were older (median age: 60 vs 55, P<.01), had similar smoking and hypertension rates, but diabetes and dyslipidemia were more prevalent (19% vs 9%, P=.01; 14% vs 6%, P=.05, respectively). In propensity score matched models for age, gender, usage of lipid lowering agents, dyslipidemia and diabetes, TDF-treated patients were more likely to show a 20% decrease in TC (95% CI: 3%-25%), LDL-C (95% CI: 1%-25%) and HDL-C (CI: 10%-30%) levels compared with those on ETV. No change in TGL was observed in either group. CONCLUSIONS: A greater decline in TC, LDL-C and HDL was observed in CHB carriers receiving TDF compared with ETV. These data may influence anti-viral choice in CHB carriers at risk for CVD.

Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy.

BACKGROUND: Ursodeoxycholic acid is widely used as the standard therapy for the treatment of primary biliary cirrhosis and other cholestatic liver diseases. Although it has been shown to improve biochemical markers and delay disease progression, its effect upon fatigue and pruritus, is at best uncertain. AIM: To assess the safety and efficacy of methotrexate for treating symptomatic primary biliary cirrhosis patients who were biochemical partial responders or non-responders to ursodeoxycholic acid therapy. METHODS: We treated eight consecutive primary biliary cirrhosis patients with methotrexate who were followed in a single hepatology clinical practice, who were symptomatic, and who had had an incomplete biochemical response to ursodeoxycholic acid therapy. Pruritus and fatigue were assessed at each clinic visit and graded from 0 (asymptomatic) to 4 (incapacitating). RESULTS: The median dose of methotrexate was 13.75 mg/week (range 7.5-15) and the mean duration of methotrexate therapy was 49 months (range 11-126). At the end of follow-up pruritus in six of seven patients had improved, and fatigue in all patients had improved with the addition of methotrexate therapy (pruritus: baseline 2.9 +/- 1.1 vs. end of treatment 0.6 +/- 1.5, P < or = 0.0175, and fatigue: baseline 3.0 +/- 0.8, vs. end of treatment 1.0 +/- 0.8, P < or = 0.0023). Improvement in symptoms was associated with a significant improvement in biochemical markers of cholestasis. No significant adverse effects of methotrexate were documented. CONCLUSIONS: Methotrexate should be considered as a potential additive treatment for symptomatic primary biliary cirrhosis patients who are incomplete biochemical responders to ursodeoxycholic acid therapy.

Effects of the neutral endopeptidase inhibitor thiorphan on cardiovascular and renal function in cirrhotic rats.

1. Cirrhosis is associated with cardiovascular and renal dysfunction including sodium retention. Many vasoactive peptides such as atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are degraded by neutral endopeptidase 24.11 (NEP). We investigated the hemodynamic and renal effects of thiorphan, a NEP inhibitor, in a rat cirrhosis model. 2. Cirrhosis was induced by chronic bile duct ligation, and controls had sham operation. Systemic and renal hemodynamics in conscious, restrained animals were determined using radiolabeled microspheres, and glomerular filtration rate (GFR) was measured by (3)H-inulin clearance. Plasma ANP and ET-1, and renal cGMP and Na(+) - K(+) ATPase activity were assayed. These variables were measured at baseline and after intravenous infusion of thiorphan (0.5 mg kg(-1) loading dose followed by 0.1 mg kg(-1) min(-1) x 30 min). 3. Thiorphan significantly decreased cardiac output, and increased systemic vascular resistance in controls, whereas in cirrhotic rats these variables were unchanged. 4. Compared to the controls, cirrhotic rats showed a decreased baseline GFR and urine sodium excretion, and the latter was significantly increased by thiorphan. 5. Thiorphan increased plasma ET-1 levels in controls, but not cirrhotic rats. ANP levels were not significantly increased in either group by thiorphan. 6. Thiorphan significantly increased cGMP concentrations and decreased Na(+) - K(+) ATPase activity of renal medulla but not cortex in cirrhotic rats; no effect was observed in the control rats. 7. We conclude that thiorphan induces natriuresis in cirrhotic rats by a direct renal medullary mechanism via cGMP and Na(+) - K(+) ATPase, without affecting systemic hemodynamics. This may potentially be useful in patients with ascites.

Sympathetic nerves, but not the adrenal gland, contribute to elevated plasma levels of met-enkephalin in rats with acute cholestatic hepatitis.

Met-enkephalin is known to circulate in human and animal plasma in low levels. However, the source(s) of plasma met-enkephalin have not been completely elucidated. It has been proposed that the adrenal gland, sympathetic nerves, pancreas and the gut might be implicated. Recently, markedly elevated levels of met-enkephalin have been documented in the presence of liver disease. To investigate potential sources of met-enkephalin in liver disease, rats with acute cholestatic hepatitis 24 h after gavage with alpha naphthylisothiocyanate (ANIT) 100 mg/kg were studied. Plasma met-enkephalin levels were determined by radioimmunoassay in plasma samples from normal, adrenalectomized, or chemically sympathectomized animals. In control rats, ANIT treatment resulted in a striking 8.7-fold increase in systemic venous met-enkephalin levels (inferior vena cava) (P < or = 0.0005) and a significant increase in peptidase-derived met-enkephalin levels (determined after trypsin/carboxypeptidase B digestion of plasma samples) (P < or = 0.05). ANIT-treatment also resulted in a 5.6-fold increase in portal vein met-enkephalin levels (P < or = 0.005). Portal vein met-enkephalin levels were only 1.2-fold higher than IVC levels in ANIT-treated rats (P < or = 0.05). Plasma activities of the two main enkephalin degrading enzymes, aminopeptidase and enkephalinase, were similar in control and ANIT-treated rats. Chemical sympathectomy, prior to ANIT treatment, decreased the elevation in inferior vena caval met-enkephalin levels by 35% (P < or = 0.005). Adrenalectomy did not alter ANIT-induced increases in circulating met-enkephalin levels (pNS).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased midbrain 5-HT1A receptor number and responsiveness in cholestatic rats.

Midbrain somatodendritic 5-HT1A autoreceptors play a central inhibitory role in the regulation of serotonergic neurotransmission. Given that serotonergic neurotransmission appears to be altered in experimental cholestatic liver disease we examined alterations in midbrain 5-HT1A autoreceptor binding and physiological responses in rats with experimental cholestatic liver disease in comparison to non-cholestatic controls. Using a standard receptor binding assay cholestatic rats exhibited an increase in midbrain 5-HT1A receptor number but no change in receptor affinity compared to controls. Midbrain 5-HT1A receptor mRNA expression as determined by semiquantitative RT-PCR was similar in cholestatic and non-cholestatic animals. In addition, cholestatic rats exhibited enhanced 5-HT1A autoreceptor-mediated hypothermic and hyperphagic responses compared to non-cholestatic controls after the administration of the highly specific 5-HT1A receptor agonist LY293284. These findings indicate that experimental cholestatic liver injury is associated with enhanced 5-HT1A autoreceptor-mediated physiological responsiveness in the setting of increased midbrain 5-HT1A receptor number but not affinity.

Methionine enkephalin accumulates in plasma but not in brain or cerebrospinal fluid of rats with acute toxic hepatitis.

In order to determine whether acute toxic hepatitis in the rat is associated with an accumulation of methionine enkephalin in plasma and increased blood-to-brain transfer of methionine enkephalin, immunoreactive methionine enkephalin levels were determined by radioimmunoassay in plasma, cerebrospinal fluid and whole brain samples from rats with thioacetamide induced acute toxic hepatitis. Thioacetamide treatment was associated with an 8.7-fold increase in plasma immunoreactive methionine enkephalin levels (P less than or equal to 0.005) 24 h after treatment. However, this marked elevation in plasma immunoreactive methionine enkephalin levels was not associated with an increase in whole brain or cerebrospinal fluid immunoreactive methionine enkephalin levels. These data suggest that increased plasma-to-brain transfer of methionine enkephalin does not occur in this model of acute toxic hepatitis.

Substrates for hypothalamic PGE2 synthesis are not decreased in cholestatic rats.

We have recently described impaired IL-1 beta-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in cholestatic rats and have implicated defective IL-1 beta-mediated hypothalamic generation of PGE2 in this finding. Since patients with obstructive cholestasis have decreased levels of PGE2 precursor fatty acids in their red blood cell membranes (arachidonic acid) we speculated that a similar deficiency of membrane prostaglandin percursor fatty acids in the hypothalamus of cholestatic rats may contribute to the defective cytokine-mediated PGE2 generation we have previously described. Therefore, in this study we determined red blood cell and hypothalamic membrane fatty acid composition in rats with obstructive cholestasis due to bile duct resection and in non-cholestatic sham resected controls 5 days after operation. To do this red blood cell membrane and hypothalamic membrane fatty acids were extracted, methyl esterified and quantified by gas liquid chromatography. Similar to results found in patients with obstructive cholestasis, bile duct resected rats had significantly reduced levels of red blood cell membrane arachidonic acid compared to levels in sham resected controls (p < or = 0.02). However, bile duct resected and sham resected rats had similar levels of hypothalamic membrane arachidonic acid. Therefore, these results suggest that the impaired IL-1 beta-induced HPA axis activation in cholestatic rats cannot be explained by lower hypothalamic membrane levels of the PGE2 substrate arachidonic acid in these animals. Furthermore, our results suggest that the brain in cholestasis appears to be protected from membrane fatty acid composition alterations which are seen outside the blood-brain-barrier.

Effect of inhibition of ornithine decarboxylase activity in a model of acute hepatocellular necrosis.

OBJECTIVE: The effect of blockade of the enzyme ornithine decarboxylase by difluoromethylornithine (DFMO) on hepatocellular necrosis and survival in rats treated with thioacetamide (TAA) was investigated. DESIGN: In one experiment, the effect of DFMO on survival of rats with TAA-induced acute hepatocellular necrosis was determined. In another experiment, blood and liver specimens were obtained from DFMO or saline-treated rats 24 h after the administration of TAA for determinations of serum alanine aminotransferase (ALT) and liver content of polyamines and microsomal cytochrome P-450 and for assessment of hepatic histology. METHODS: Liver polyamines were determined by reversed-phase HPLC and microsomal cytochrome P-450 content by dithionite-difference spectroscopy of CO-treated homogenates. The severity of hepatocellular necrosis was scored blindly. RESULTS: TAA-treated rats that received DFMO survived longer than saline-treated controls (P < 0.01). Serum ALT and liver putrescine concentrations were lower and the histological severity of acute hepatocellular necrosis was less in DFMO-treated rats with TAA-induced hepatocellular necrosis than in saline-treated controls (P < 0.05, P < 0.01 and P < 0.05, respectively). Total cytochrome P-450 levels were similar in DFMO and saline-treated rats with TAA-induced hepatocellular necrosis. CONCLUSIONS: DFMO increases survival in TAA-induced fulminant hepatic failure by decreasing the severity of acute hepatocellular necrosis. The beneficial effects of DFMO do not appear to be mediated by its effects on polyamine metabolism, but may be attributable to an effect of DFMO on thioacetamide metabolism or on an alternative pathway of ornithine metabolism.

Reactivation of hepatitis B e antigen-negative chronic hepatitis B in a bone marrow transplant recipient following lamivudine withdrawal.

Reactivation of hepatitis B virus (HBV) is a recognized complication of bone marrow transplantation (BMT). Lamivudine is a nucleoside analogue with potent antiviral activity that has been used in the prophylaxis of HBV reactivation in at-risk BMT recipients. Currently, no data exist regarding the safety of nucleoside analogue withdrawal in these patients. A 32-year-old BMT recipient with hepatitis B e antigen (HBeAg)-negative, chronic HBV who developed a serious flare of hepatic inflammation due to a rebound in viral replication within 12 weeks of discontinuing lamivudine therapy is described. The patient remained HBeAg-negative despite high level viremia, suggesting the emergence of a mutant viral strain. The patient's acute hepatitis resolved promptly with the reinstitution of lamivudine therapy. Further studies are necessary to define the safety and efficacy of nucleoside analogues in the prevention of HBV reactivation in at-risk BMT recipients. Clinicians should consider the risk of inducing serious flares of hepatic inflammation due to abrupt nucleoside analogue withdrawal in these patients.

Fatigue in chronic disease.

Fatigue is an extremely common complaint among patients with chronic disease. However, because of the subjective nature of fatigue, and the lack of effective therapeutics with which to treat fatigue, this symptom is often ignored by clinicians, who instead focus on hard, objective disease end-points. Recently, the symptom of fatigue has received greater attention as part of overall health-related quality of life assessments in patients with chronic disease. Furthermore, new methods are being developed to help quantify fatigue, and are being utilized more frequently in the clinical setting. Moreover, studies in patients and using animal models of disease have provided some insight into changes within the brain which appear to be linked to the genesis of central fatigue. This review focuses on fatigue in chronic disease and outlines possible mechanisms which may give rise to central fatigue in chronic disease. Moreover, methods for measuring fatigue and an approach to the fatigued patient are discussed. Hopefully, a broader understanding of this distressing symptom will lead to the development of specific therapies for treating fatigue in these patients.

Alterations in hypothalamic mu-opiate receptor-mediated responses but not methionine enkephalin or proenkephalin messenger RNA levels in rats with acute cholestasis.

Endogenous opioids, including methionine enkephalin, have been implicated in the control of adrenocorticotrophic hormone release by acting through mu-opiate receptors in the hypothalamus. Recently, alterations in the central opioid system have been postulated to occur in cholestasis. In addition, alterations in hypothalamic corticotropin-releasing hormone content and messenger RNA levels, as well as basal release, have been described in bile duct-resected rats, and hypothalamic methionine enkephalin is colocalized with corticotropin-releasing hormone in hypothalamic neurons. Therefore hypothalamic and pituitary methionine enkephalin content and hypothalamic proenkephalin messenger RNA levels, as well as hypothalamic mu-opiate receptor-mediated responses in vitro and in vivo, were studied in rats with acute cholestasis caused by bile duct resection and in respective controls. Hypothalamic and pituitary methionine enkephalin levels were similar in bile duct-resected, sham-resected and unoperated control rats. In addition, hypothalamic proenkephalin steady state messenger RNA levels were similar in the three groups of animals. mu-Opiate receptor stimulation of hypothalamic explants in vitro with the specific mu-opiate receptor agonist ligand [D-Ala2,N-Me-Phe4,Gly-ol]-Enkephalin resulted in 8.2% and 16.9% inhibition of corticotropin-releasing hormone release in sham-resected and unoperated control rats, respectively. In contrast, treatment of hypothalamic explants from bile duct-resected rats with [D-Ala2,N-Me-Phe4,Gly-ol]-Enkephalin resulted in a significant 22.5% increase in corticotropin-releasing hormone release. Systemic administration of the mu-opiate receptor agonist morphine to rats in vivo resulted in significantly higher incremental rises in plasma adrenocorticotropic hormone levels in sham-resected and unoperated control animals than in bile duct-resected rats.(ABSTRACT TRUNCATED AT 250 WORDS)

I. Stress and hepatic inflammation.

Stress is an ever-present part of modern life. The "stress response" constitutes an organism's mechanism for coping with a given stress and is mediated via the release of glucocorticoids and catecholamines. Patients often complain of stress-related worsening of their liver disease; however, the interrelationship between stress and hepatic inflammation is incompletely understood and has received little scientific attention. Considering the broad impact glucocorticoids and catecholamines have on immune cell function, it is very likely that stress has a significant impact on the hepatic inflammatory response. This themes article discusses studies of the stress response and its peripheral effectors (glucocorticoids and catecholamines) in liver disease and their impact on hepatic inflammation and outlines potential areas for future scientific investigation.

Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat.

BACKGROUND & AIMS: Abnormal presentation of luminal constituents to the mucosal immune system, caused by dysfunction of the intestinal epithelial barrier, is a candidate theory for the cause of Crohn's disease. Increased epithelial permeability is found in subgroups of patients at high risk for the development of Crohn's disease and has been found to precede disease recurrence. Clinical observations have suggested that disease recurrence can follow times of increased psychological stress, although the underlying mechanism remains obscure. We hypothesized that environmental stress increases gastrointestinal permeability. METHODS: We evaluated site-specific gastrointestinal permeability after application of graded levels of stress in rats. RESULTS: Increased epithelial permeability after stress was shown in all regions of the gastrointestinal tract and seemed to be mediated by adrenal corticosteroids. Stress-induced increases in epithelial permeability disappeared after adrenalectomy or pharmacologic blockade of glucocorticoid receptors. Dexamethasone treatment of control animals increased gastrointestinal permeability and mimicked the effects of stress. CONCLUSIONS: Psychological stress may increase gastrointestinal permeability, allowing luminal constituents access to the mucosal immune system. This provides a potential mechanism for the observation of stress-induced disease recurrence in Crohn's disease.

Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment.

Fatigue is a common complaint in patients with liver disease; however, the etiology of fatigue is poorly understood and no therapeutic options are available to treat it. Altered central neurotransmission, especially serotonergic, appears to play a role in the genesis of fatigue. In this study, we describe a rat model of fatigue assessment using a swim tank, and we used this model to document the degree of fatigue in rat models of cholestasis caused by bile duct resection (BDR) and of hepatitis caused by carbon tetrachloride (CCl4) administration. Fatigue was quantitated as the time spent floating and struggling over a 15-minute period after placement in the swim tank, and an overall activity score was calculated. Using this technique, BDR rats exhibited significantly enhanced floating times and an overall reduction in activity score compared with noncholestatic controls (P < or = .01). On the other hand, CCl4-treated rats showed a marked variability in floating and struggling times and activity scores such that, overall, CCl4-treated rats were not significantly different from normal controls. Therefore, we used BDR and noncholestatic control rats to examine the effects of a serotonin (5HT1A) receptor agonist (LY293284) on cholestasis-associated fatigue. BDR rats treated with LY293284 (0.3 mg/kg subcutaneously 24, 5, and 1 hour before placement in the swim tank) showed marked reductions in floating times and an increase in overall activity scores compared with BDR controls (P < or = .001). LY293284 was without effect in noncholestatic animals. These results suggest that fatigue can be quantitated in rat models of liver disease and that 5HT1A receptor agonists may provide a useful therapeutic tool in the treatment of cholestatic liver disease-associated fatigue.

Defective corticotropin-releasing hormone mediated neuroendocrine and behavioral responses in cholestatic rats: implications for cholestatic liver disease-related sickness behaviors.

Nonspecific systemic complaints are commonly encountered in patients with cholestatic liver diseases. However, the cause of these symptoms is poorly understood. Because corticotropin-releasing hormone (CRH) has been implicated as a mediator of sickness-related systemic symptoms, we examined CRH-mediated neuroendocrine and behavioral responses in rats with cholestasis due to bile duct resection (BDR) or sham resected (sham) controls. BDR and sham rats were placed individually in an open field apparatus, and the number of inner and outer squares entered, as well as the number of fecal boli produced, counted over a 5-minute period. Fecal boli production and inner squares entered are dependent on central CRH release. BDR and sham rats entered the same number of outer squares; however, BDR rats entered significantly fewer inner squares and produced fewer fecal boli than did sham rats, suggesting defective central CRH release in BDR rats. Immediately after exposure to the open field, rats were killed and blood adrenocorticotropic hormone (ACTH) levels measured. ACTH release is dependent on central CRH release. BDR rats demonstrated significantly lower plasma ACTH levels after exposure to an open field than did sham animals. To further explore the central CRH defect in BDR rats, hypothalamic CRH contents were determined in BDR and sham rats with and without exposure to restraint stress. BDR rats had significantly lower basal hypothalamic CRH levels than sham animals, and CRH levels did not further decrease in BDR rats with restraint stress (as normally occurs). These results are consistent with defective CRH-mediated responses in cholestatic rats.(ABSTRACT TRUNCATED AT 250 WORDS)