[The descending pathophysiology model of cholestatic liver disease].

Intrahepatic cholestasis is a pathological condition in which the synthesis, secretion, and excretion of bile are blocked, and thus the bile does not flow normally into the duodenum and bloodstream. According to cytological damage site, it can be divided into hepatocellular cholestasis, biliary duct cell cholestasis and mixed cell cholestasis. The two kinds of pathophysiological models [ascending or upstream (damage begins with cholangiocytes and then extends to the hepatocytes) and descending or downstream (the damage starts from the liver cells and then extends to the bile duct cells)] has distinct features in the process of disease occurrence and development. This article mainly elaborates the "descending" pathophysiological model of cholestatic liver disease (hepatocytic damage progresses to biliary duct cell), and further explores its etiology, pathogenesis and treatment methods.

Jaundice in the emergency department: meeting the challenges of diagnosis and treatment [digest].

There are approximately 52,000 visits a year to emergency departments for patients presenting with jaundice. While many of these patients will not have immediately life-threatening pathology, it is essential that the emergency clinician understands the pathophysiology of jaundice, as this will guide the appropriate workup to detect critical diagnoses. Patients who present with jaundice could require intravenous antibiotics, emergent surgery, and, in severe cases, organ transplantation. This issue will focus on the challenge of evaluating and treating the jaundiced patient in the ED using the best available evidence from the literature. [Points & Pearls is a digest of Emergency Medicine Practice.].

Jaundice in the emergency department: meeting the challenges of diagnosis and treatment.

There are approximately 52,000 visits a year to emergency departments for patients presenting with jaundice. While many of these patients will not have immediately life-threatening pathology, it is essential that the emergency clinician understands the pathophysiology of jaundice, as this will guide the appropriate workup to detect critical diagnoses. Patients who present with jaundice could require intravenous antibiotics, emergent surgery, and, in severe cases, organ transplantation. This issue will focus on the challenge of evaluating and treating the jaundiced patient in the ED using the best available evidence from the literature.

Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

Effect of probiotic supplementation on bacterial translocation in common bile duct obstruction.

OBJECTIVE: To investigate the effects of probiotics on bacterial translocation in the obstructive common bile duct with comparison to an enteral product containing arginine and glutamine. MATERIAL AND METHOD: In our study, 40 Sprague-Dawley rats each weighing 250-300 g were used. Animals in Group 1 (sham) were laparatomized and fed standard chow supplemented with physiologic saline at daily doses of 2 ml through orogastric tube for 7 days. Common bile ducts of the animals in the other groups were ligated with 3/0 silk sutures. Group 2 (control group) was fed standard chow supplemented with daily doses of 2 ml physiologic saline. Group 3 (probiotic group) was fed standard chow supplemented with a probiotic solution (Acidophilus plus) containing strains of Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus bulgaricus at a daily doses of 2 × 10(9) colony forming units (CFU). Group 4 (formula group) was fed only an enteral solution (Stresson Multi Fiber) containing glutamine, arginine and a medium-chain fatty acid at daily doses of 2 g/kg. At the end of the 7th day, all animals were relaparatomized, and to determine bacterial translocation, aerobic, and anaerobic cultures were obtained from the specimens of mesenteric lymph nodes, intestinal mucosa, and blood samples. Smear cultures prepared from caecum were examined to determine the number of CFU. Finally, for histological examination specimens were excised from terminal ileum, and oxidative damage was assessed in liver tissues. Afterwards all animals were killed. RESULTS: Moderately lesser degrees of bacterial translocation, and mucosal damage were seen in Groups 3, and 4 relative to Group 2 (p < 0.05). In Group 4, any difference was not seen in the number of cecal bacteria relative to baseline values, while in Group 3, significant decrease in cecal colonization was seen. Among all groups, a significant difference between levels of malondialdehyde, and glutathione was not observed. CONCLUSION: At the end of our study, we have concluded that both probiotics, and enteral diets which contain immunomodulators such as glutamine, and arginine alleviate bacterial translocation, and impairment of intestinal mucosa.

Influence of distal ileum exclusion on hepatic and renal functions in presence of extrahepatic cholestasis.

OBJECTIVE: To verify whether the ileal exclusion interferes with liver and kidney functional changes secondary to extrahepatic cholestasis. METHODS: We studied 24 rats, divided into three groups with eight individuals each: Group 1 (control), Group 2 (ligation of the hepatic duct combined with internal biliary drainage), and Group 3 (bile duct ligation combined with internal biliary drainage and exclusion of the terminal ileum). Animals in Group 1 (control) underwent sham laparotomy. The animals of groups 2 and 3 underwent ligation and section of the hepatic duct and were kept in cholestasis for four weeks. Next, they underwent an internal biliary bypass. In Group 3, besides the biliary-enteric bypass, we associated the exclusion of the last ten centimeters of the terminal ileum and carried out an ileocolic anastomosis. After four weeks of monitoring, blood was collected from all animals of the three groups for liver and kidney biochemical evaluation (albumin, ALT, AST, direct and indirect bilirubin, alkaline phosphatase, cGT, creatinine and urea). RESULTS: there were increased values of ALT, AST, direct bilirubin, cGT, creatinine and urea in rats from Group 3 (p < 0.05). CONCLUSION: ileal exclusion worsened liver and kidney functions in the murine model of extrahepatic cholestasis, being disadvantageous as therapeutic procedure for cholestatic disorders.

Influence of distal ileum exclusion on hepatic and renal functions in presence of extrahepatic cholestasis / Influência da exclusão do íleo terminal nas funções hepáticas e renais em presença de colestase extra-hepática

OBJECTIVE: To verify whether the ileal exclusion interferes with liver and kidney functional changes secondary to extrahepatic cholestasis. METHODS: We studied 24 rats, divided into three groups with eight individuals each: Group 1 (control), Group 2 (ligation of the hepatic duct combined with internal biliary drainage), and Group 3 (bile duct ligation combined with internal biliary drainage and exclusion of the terminal ileum). Animals in Group 1 (control) underwent sham laparotomy. The animals of groups 2 and 3 underwent ligation and section of the hepatic duct and were kept in cholestasis for four weeks. Next, they underwent an internal biliary bypass. In Group 3, besides the biliary-enteric bypass, we associated the exclusion of the last ten centimeters of the terminal ileum and carried out an ileocolic anastomosis. After four weeks of monitoring, blood was collected from all animals of the three groups for liver and kidney biochemical evaluation (albumin, ALT, AST, direct and indirect bilirubin, alkaline phosphatase, cGT, creatinine and urea). RESULTS: there were increased values of ALT, AST, direct bilirubin, cGT, creatinine and urea in rats from Group 3 (p < 0.05). CONCLUSION: ileal exclusion worsened liver and kidney functions in the murine model of extrahepatic cholestasis, being disadvantageous as therapeutic procedure for cholestatic disorders. .

OBJETIVO: verificar se a exclusão ileal interfere nas alterações funcionais hepáticas e renais, secundárias à colestase extra-hepática. MÉTODOS: foram estudados 24 ratos, distribuídos em três grupos (n=8): Grupo 1 (controle), Grupo 2 (ligadura do ducto hepático combinada com drenagem biliar interna) e Grupo 3 (ligadura do ducto hepático combinada com drenagem biliar interna e exclusão do íleo terminal). Os animais do Grupo 1 (controle) foram submetidos a laparotomia e laparorrrafia. Os animais dos grupos 2 e 3 foram submetidos a ligadura e secção do ducto hepático e mantidos em colestase por oclusão biliar durante quatro semanas. A seguir, foram submetidos a derivação biliar interna. No Grupo 3, associou-se a exclusão dos últimos dez centímetros do íleo terminal e anastomose ileocólica à derivação biliodigestiva. Após outras quatro semanas de acompanhamento, foi colhido sangue de todos os animais dos três grupos, para avaliação bioquímica do fígado e dos rins (albumina, ALT, AST, bilirrubinas direta e indireta, fosfatase alcalina, cGT, creatinina e ureia). RESULTADOS: houve aumento dos valores de ALT, AST, bilirrubina direta, cGT, creatinina e ureia nos ratos do Grupo 3 (p < 0,05). CONCLUSÃO: no modelo murino de colestase extra-hepática, a exclusão ileal piorou as funções hepáticas e renais, sendo desvantajosa como proposta terapêutica para afecções colestáticas. .

La X de las dislipemias / The "x" of dyslipemias

Los pacientes con colestasis hepática pueden presentar hipercolesterolemia secundaria, como consecuencia de la acumulación de la lipoproteína X (Lp-X); una forma anómala de LDL, considerada como el parámetro bioquímico más sensible y específico para el diagnóstico de colestasis intra o extrahepática. El objetivo de esta comunicación clínica es ilustrar esta asociación. Se trata de un varón de 54 años con hepatopatía colestásica severa que a su vez presenta una elevación progresiva de colesterol total y LDL con presencia de lipoproteína X. El colesterol total y LDL, descendieron progresivamente hasta normalizarse, coincidiendo con la mejoría de la función hepática, confiriendo un patrón de protección cardiovascular (AU)

Patients with cholestatic diseases can present secondary hypercholesterolemia, as a result of the accumulation of lipoprotein X (Lp-X); an abnormal LDL form, considered as the biochemical parameter more sensitive and specific for the diagnosis of cholestasis intra or extrahepatic cholestasis. The aim of this clinical comunication is to illustrate this association. A 54-year-old male with severe cholestatic liver disease wich in turn presents a progressive total cholesterol rise and LDL with presence of lipoprotein X. Total and LDL cholesterol were down to normal, also coinciding with the improvement of cholestatic liver disease conferring cardiovascular protection pattern (AU)

[Effect of biliary obstruction on lipoprotein(a) concentration]. / Efecto de la obstrucción de la vía biliar en la concentración de lipoproteína(a).

OBJECTIVES: This study was appointed to determine the correlation between the concentration of lipoprotein(a) [Lp(a)], apolipoproteins and lipids with biochemical parameters of liver function in a group of patients with reversible cholestasis. We have also determined the concentration of these parameters once solved the biliary obstruction process. MATERIAL AND METHODS: Eighteen adults over 17 years with extrahepatic cholestasis were included in the study on a prospective basis, and we determined in them biochemical liver function parameters and lipoprotein metabolism parameters, particularly Lp(a) before and after unblocking. RESULTS: The concentration of Lp(a) prior to desobstruction was inverse and statistically significantly correlated with the concentration of gamma glutamyl transpeptidase (correlation coefficient [r] = -0.757, P = .018). The concentration of Lp(a) (median = 2.66 mg/dL, interquartile range = 5,62) showed a statistically significant increase (median = 9.72 mg/dL, interquartile range = 28.76, P < .001), once the unblocking was performed. Concentrations of total cholesterol and triglycerides had a statistically significant decrease, and HDL cholesterol and apolipoprotein A-1 showed a statistically significant increase once the unblocking was carried out. CONCLUSIONS: The concentration of Lp(a) is decreased during cholestasis, although there is a significant simultaneous hypercholesterolemia. Cholestasis has a causal role in lowering Lp(a), because the unblocking of bile duct recovers Lp(a) concentration. Our study supports the concept that bile acids exert a controlling effect on the synthesis of Lp(a) and open a mechanism for the treatment of hyper Lp(a).

Liver radiofrequency ablation compromises the biological gut barrier.

AIM: Liver radiofrequency ablation (RFA) has been shown to disrupt the mechanical component of the gut barrier. The aim of the present study was to investigate the consequences of liver RFA on the biological gut barrier in terms of the effects of bile production rate and bowel inflammatory state on intestinal microflora balance. METHOD: A total of 25 New Zealand rabbits were assigned to five groups (n = 5 per group): group CBD: subjected to common bile duct (CBD) extracorporeal bypass; group CBD-RFA: subjected to CBD bypass plus one session of open liver RFA; group RFA: subjected to liver RFA; group sham: subjected to sham operation; and group TBD: subjected to total bile deviation (TBD). In groups CBD and CBD-RFA, bile production rate was assessed for 48 h. In groups sham and RFA, measurement of biliary glycine conjugates of cholic and deoxycholic acid levels, histopathologic examination of the non-ablated liver tissue, morphometric analysis, and histopathologic examination of the terminal ileum and microbiological analysis of fecal and tissue samples collected from the jejunum and the cecum (and in group TBD) were performed at 48 h post-operation. RESULTS: One session of liver RFA resulted in ablation of 18.7 ± 2.7% of liver weight. Following liver RFA, bile production rate was reduced, while the levels of biliary bile salts were not affected. There was mild injury of the non-ablated liver parenchyma, mild intestinal wall inflammation, intestinal mucosa atrophy, and intestinal microbial population overgrowth. CONCLUSION: Reduced in bile production and mild bowel inflammation secondary to liver RFA impaired the biological gut barrier as manifested by intestinal microflora imbalance.

The effect of ursodeoxycholic acid on oxidative stress level and DNase activity in rat liver after bile duct ligation.

Accumulation of hydrophobic bile acids (BAs) during cholestasis plays an important role in apoptosis initiation as well as oxidative stress increase in liver cells. Ursodeoxycholic acid (UDCA) acts as a protector in BA-induced cell injury.The aim of the study was to evaluate the effect of UDCA on oxidative stress level and DNase I and II activity caused by liver injury in bile duct ligation (BDL) rats.Wistar rats were divided in four groups: group 1, control (sham-operated); group 2, sham-operated and injected with UDCA (30 mg/kg); group 3,animals with BDL; and group 4,UDCA-treatedcholestatic rats. Animals were sacrificed after 9 days. Malondialdehyde (MDA; lipid peroxidation end-product) level and protein-molecule oxidative modification (carbonyl group content) significantly increased in BDL rat liver. Catalase (CAT) activity in liver tissue was found to be decreased in BDL rats. In addition, xanthine oxidase (XO) activity, which is thought to be one of the key enzymes producing reactive oxygen species, was found to be increased in the cholestatic group. The apoptotic effect in cholestasis was probably triggered by the increased activation of DNase I and II. The protective effect of UDCA on liver tissue damage in BDL rats, in comparison to cholestatic liver, were 1) decrease of MDA levels, 2) increased CAT activity, 3) reduced XO activity, and 4) effect on terminal apoptotic reaction, shown as a decrease in DNase I and II activity.Therefore, UDCA may be useful in the preservation of liver function in cholestasis treatment.

Restoration of hepatocytes function following decompression therapy in extrahepatic biliary obstructed patients: metabolite profiling of bile by NMR.

Prolonged biliary obstruction and infection cause retention of biliary constituents in liver followed by hepatocyte dysfunction. Decompression therapy is important for both management and prognostic reasons and restores hepatocyte function. Quantitative metabolite profiling of bile using NMR spectroscopy at the time of obstruction and serially following decompression therapy using percutaneous transhepatic biliary drainage (PTBD) from nineteen patients with extrahepatic malignant biliary obstruction are presented. Based on detailed history, clinical condition, total leucocyte counts (TLC) and microbiological cultures of bile, patients were classified in two groups depending upon absence or presence of cholangitis. Statistical analysis was performed for comparison within each group using Wilcoxan sign square rank test. TLC and liver function tests indicated a trend towards recovery following decompression by one week. While on day 0 biliary constituents were undetectable in both the groups of patients, they increased significantly following one week of drainage with better recovery in patients with cholangitis compared to without. Free amino acids' signals were detected in all specimens starting from day 1 after decompression. This indicates disruption of blood-bile barrier during cholestasis and slow restoration of tight junction of hepatocytes following decompression leading to the appearance of biliary constituents in bile. Decompression therapy tends to restore biliary constituents with a prompt recovery in patients with cholangitis further supports such therapy for clinical management and outcome. To our knowledge this is the first report on the detection of amino acids in bile taken from common bile duct though they have been reported in hepatic bile.

Influence of glutamine on morphological and functional changes of liver in the presence of extrahepatic biliary obstruction in rats.

PURPOSE: To study the influence of glutamine on functional and morphological changes of liver in the extrahepatic biliary obstruction through an experimental model in rats. METHODS: Seventy Wistar rats were divided into four groups: control (group C) fictitious operation, (group FO), submitted to laparotomy with handling of bile ducts, but without hepatic duct ligation, (group EBO) submitted to laparotomy and hepatic duct ligation, one of them submitted to supplementation with glutamine 2% (group G). The control group consisted of 6 animals. The animals from groups FO, EBO and G were divided into three groups consisting of 6 animals each, being sacrificed at 7, 14 and 21 days after operation, respectively. Blood samples were collected for biochemical analysis and a fragment of liver tissue was collected from the middle lobe for histological analysis. RESULTS: Both for biochemical analysis (BT, aspartate and alanine aminotransferase AST, ALT and alkaline phosphatase FAL) and for histopathological changes (fibrosis, portal inflammation, parenchymal inflammation, hepatocytic changes and duct proliferation), no statistical difference between groups submitted to extrahepatic biliary obstruction (EBO) with and without treatment with glutamine (G) was observed. CONCLUSION: Glutamine supplementation did not alter the prognosis of liver enzymes and histopathological changes in animals submitted to extrahepatic biliary obstruction.

Influence of glutamine on morphological and functional changes of liver in the presence of extrahepatic biliary obstruction in rats / Influência da glutamina em alterações funcionais e morfológicas do fígado na vigência de obstrução biliar extra-hepática em ratos

PURPOSE: To study the influence of glutamine on functional and morphological changes of liver in the extrahepatic biliary obstruction through an experimental model in rats. METHODS: Seventy Wistar rats were divided into four groups: control (group C) fictitious operation, (group FO), submitted to laparotomy with handling of bile ducts, but without hepatic duct ligation, (group EBO) submitted to laparotomy and hepatic duct ligation, one of them submitted to supplementation with glutamine 2 percent (group G). The control group consisted of 6 animals. The animals from groups FO, EBO and G were divided into three groups consisting of 6 animals each, being sacrificed at 7, 14 and 21 days after operation, respectively. Blood samples were collected for biochemical analysis and a fragment of liver tissue was collected from the middle lobe for histological analysis. RESULTS: Both for biochemical analysis (BT, aspartate and alanine aminotransferase AST, ALT and alkaline phosphatase FAL) and for histopathological changes (fibrosis, portal inflammation, parenchymal inflammation, hepatocytic changes and duct proliferation), no statistical difference between groups submitted to extrahepatic biliary obstruction (EBO) with and without treatment with glutamine (G) was observed. CONCLUSION: Glutamine supplementation did not alter the prognosis of liver enzymes and histopathological changes in animals submitted to extrahepatic biliary obstruction.

OBJETIVO: Estudar a influência da glutamina em alterações funcionais e morfológicas do fígado na obstrução biliar extra-hepática por meio de um modelo experimental desenvolvido em ratos. MÉTODOS: Setenta ratos Wistar distribuídos em quatro grupos: controle (grupo C); operação fictícia (grupo OF), submetido à laparotomia com manuseio das vias biliares, mas sem ligadura do ducto hepático; (grupo OBE), submetido à laparotomia exploradora e ligadura do ducto hepático, sendo um deles submetido à suplementação com glutamina a 2 por cento (grupo G). O grupo controle era composto por seis animais. Os animais dos grupos OF, OBE e G foram divididos em três grupos compostos por seis animais cada e que foram sacrificados no 7°, 14° e 21° dias após a operação, respectivamente. Foi colhido sangue para análise bioquímica e um fragmento de tecido hepático do lobo médio para estudo histológico. RESULTADOS: Tanto em relação à analise bioquímica (BT, aspartate and alanine aminotransferase AST, ALT e FAL) quanto em relação às alterações histopatológicas (fibrose, inflamação portal, inflamação parenquimatosa, alterações hepatocíticas e proliferação de ducto), não houve diferença estatística entre os grupos submetido a obstrução biliar extra-hepática sem (OBE) e com tratamento com glutamina (G). CONCLUSÃO: A suplementação com glutamina não alterou o prognóstico em relação às enzimas hepáticas e alterações histopatológicas nos animais submetidos à obstrução biliar extra-hepática.

Divergent effects of irritants on the gastric mucosa in rats during various stages after bile duct ligation.

BACKGROUND AND AIM: Controversy exists as to whether rats after bile duct ligation (BDL) are more susceptible to gastric mucosal damage (GMD) induced by irritants. In the present study we characterize GMD after intragastric instillation of either ethanol or hydrochloric acid (HCL), 3 and 21 days after the surgical procedure. METHODS: Bile duct ligation and sham operated (SO) rats were studied. RESULTS: Three days after surgery, BDL rats exhibited a reduction in gastric mucosal nitric oxide synthase (NOS) activity but an increase in ethanol-induced GMD. Twenty-one days after surgery gastric mucosal prostaglandin (PG) E(2) generation in BDL rats was increased while NOS activity in both groups was similar. Ethanol-induced GMD in SO rats was higher. Pretreatment with NG-nitro-L-arginine methyl ester, prior to ethanol administration was associated with an increase in gastric mucosal PGE(2) generation: (147% in SO and 104% in BDL rats) and in GMD (176% in SO and 303% in BDL rats). HCL induced GMD was of similar magnitude in both groups in both time periods. CONCLUSIONS: The gastric resistance to damage by irritants in rats with BDL is not a static phenomenon. This may result from sequential changes that occur in the gastric mucosal defense mechanisms during the evolution of liver disease.

Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice.

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-α (10 µg/kg i.p.) or physiological saline every third day, beginning 24 h after BDL. Mice were killed at 2, 5, 14, and 28 days after BDL. Beside hematological parameters, markers of inflammation and fibrosis were assessed histomorphometrically and immunohistochemically as well as by quantitative real-time PCR. In addition, a 7-week survival study was performed. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased expression of profibrotic gene transcripts. Darbepoetin-α treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, decreased levels of profibrotic genes, and lowered collagen deposition. Moreover, darbepoetin-α significantly reduced systemic anemia caused by BDL. Finally, darbepoetin-α treatment significantly prolonged the survival time after BDL. This study suggests that darbepoetin-α, which is a clinically well-established substance, might be used as an efficient therapeutic option for patients with chronic cholestatic liver disease.

Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation.

BACKGROUND AND PURPOSE: We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. EXPERIMENTAL APPROACH: Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. KEY RESULTS: Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. CONCLUSIONS AND IMPLICATIONS: The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.

Predictive value of assessment of different modalities in the diagnosis of infantile cholestasis.

This study investigated the relative accuracy and roles of abdominal ultrasonography, hepatobiliary scintigraphy and liver biopsy in the diagnosis of infantile cholestasis. A total of 50 infants (27 females) aged 1 - 12 months were classified into those with intrahepatic causes of cholestasis (n = 22) and those with extrahepatic causes (n = 28). Cholestasis is caused by a wide range of conditions and diagnosis requires meticulous history taking, thorough clinical examination and many laboratory tests. The most common cause of intrahepatic cholestasis was found to be idiopathic neonatal hepatitis (54.5%), followed by infectious hepatitis (9.1%), metabolic liver diseases (9.1%), intrahepatic biliary atresia (9.1%) and Alagille syndrome (4.5%). The most common cause of extrahepatic cholestasis was extrahepatic biliary atresia (96.4%). The incidence of choledochal cyst was low (3.6%). The cornerstone of the diagnosis of infantile cholestasis was found to be liver biopsy, which was associated with a high degree of accuracy.

Bile duct ligation: step-by-step to cholangiocyte inflammatory tumorigenesis.

Chronic liver inflammation after murine bile duct ligation could evolve according to three interrelated phenotypes, which would have different metabolic, functional and histologic characteristics. Liver injury secondary to extrahepatic cholestasis would induce an early ischemic-reperfusion phenotype with cholangiocyte depolarization, abnormal ion transport, hypometabolism with anaerobic glycolysis and hepatocytic apoptosis. This phenotype, in turn, could trigger the switch to a leukocytic phenotype by the cholangiocytes, with an intense anaplerotic activity, hypermetabolism, extracellular matrix degradation and moderated proliferation to create a pseudotissue with metabolic autonomy and paracrine functions. In the long-term cholestasis-drive tumorigenesis, the tumorous tissue would principally consist of cholangiocyte parenchyma, with an impressive biosynthetic activity through the tricarboxylic cell cycle. In terms of the tumorous stroma, made up by fibroplasia and angiogenesis, it would favor the tumor trophism. In conclusion, the great intensity and persistence in the expression of these phenotypes by the cholestatic cholangiocyte would favor chronic inflammatory tumorigenesis.