Implication des protéines des gouttelettes lipidiques dans la résistance a l'insuline hépatique. [Involvement of protein lipid droplets in the resistance to hepatic insulin.]

Introduction : La prévalence des maladies stéatosiques non alcooliques du foie augmente de manière exponentielle dans les pays industrialisés. Le développement de ces maladies se traduit par une stéatose hépatique fréquemment associée à une résistance à l'insuline. Cette résistance a pu être expliquée par l'accumulation intra-hépatocytaire de lipides intermédiaires tels que Céramides et Diacylglycérols. Cependant, notre modèle animal de stéatose hépatique, les souris invalidées pour la protéine hépatique « Microsomal Triglyceride Transfert Protein » (Mttp Δ / Δ), ne développent pas de résistance à l'insuline, malgré une augmentation de ces lipides intermédiaires. Ceci suggère la présence d'un autre mécanisme induisant la résistance à l'insuline. Matériels et méthodes : L'analyse Microarray du foie des souris Mttp Δ / Δ a montré une forte up-régulation des gènes « Cell-death Inducing DFFA-like Effector C (cidec) », « Lipid Storage Droplet Protein 5 (lsdp5) » et « Bernardinelli-Seip Congenital Lipodystrophy 2 Homolog (seipin) » dans le foie des souris Mttp Δ / Δ. Ces gènes ont été récemment identifiés comme codant pour des protéines structurelles des gouttelettes lipidiques. Nous avons testé si ces gènes jouaient un rôle important dans le développement de la stéatose hépatique, ainsi que de la résistance à l'insuline. Résultats : Nous avons démontré que ces gènes sont fortement augmentés dans d'autres modèles de souris stéatosées tels que ceux présentant une sur-expression de ChREBP. Dans les hépatocytes murins (AML12 :Alfa Mouse Liver 12), l'invalidation de cidec et/ou seipin semble diminuer la phosphorylation d'AKT après stimulation à l'insuline, suggérant une résistance à l'insuline. Chez l'homme, l'expression de ces gènes est augmentée dans le foie de patients obèses avec stéatose hépatique. De manière intéressante, cette augmentation est atténuée chez les patients avec résistance à l'insuline. Conclusion : Ces données suggèrent que ces protéines des gouttelettes lipidiques augmentent au cours du développement de la stéatose hépatique et que cette augmentation protège contre la résistance à l'insuline.

Assessment of therapeutic benefit of antiviral therapy in chronic hepatitis C: is hepatic venous pressure gradient a better end point?

Chronic hepatitis C is a major healthcare problem. The response to antiviral therapy for patients with chronic hepatitis C has previously been defined biochemically and by PCR. However, changes in the hepatic venous pressure gradient (HVPG) may be considered as an adjunctive end point for the therapeutic evaluation of antiviral therapy in chronic hepatitis C. It is a validated technique which is safe, well tolerated, well established, and reproducible. Serial HVPG measurements may be the best way to evaluate response to therapy in chronic hepatitis C.

CO2 wedged hepatic venography in the evaluation of portal hypertension.

BACKGROUND/AIMS/METHODS During hepatic vein catheterisation, in addition to measurement of hepatic venous pressure gradient (HVPG), iodine wedged retrograde portography can be easily obtained. However, it rarely allows correct visualisation of the portal vein. Recently, CO2 has been suggested to allow better angiographic demonstration of the portal vein than iodine. In this study we investigated the efficacy of CO2 compared with iodinated contrast medium for portal vein imaging and its role in the evaluation of portal hypertension in a series of 100 patients undergoing hepatic vein catheterisation, 71 of whom had liver cirrhosis. RESULTS In the overall series, CO2 venography was markedly superior to iodine, allowing correct visualisation of the different segments of the portal venous system. In addition, CO2, but not iodine, visualised portal-systemic collaterals in 34 patients. In cirrhosis, non-visualisation of the portal vein on CO2 venography occurred in 11 cases; four had portal vein thrombosis and five had communications between different hepatic veins. Among non-cirrhotics, lack of portal vein visualisation had a 90% sensitivity, 88% specificity, 94% negative predictive value, and 83% positive predictive value in the diagnosis of pre-sinusoidal portal hypertension. CONCLUSIONS Visualisation of the venous portal system by CO2 venography is markedly superior to iodine. The use of CO2 wedged portography is a useful and safe complementary procedure during hepatic vein catheterisation which may help to detect portal thrombosis. Also, lack of demonstration of the portal vein in non-cirrhotic patients strongly suggests the presence of pre-sinusoidal portal hypertension.

Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.

We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.

Upper gastrointestinal bleeding in cirrhosis: clinical and endoscopic correlations

The clinical data of 180 episodes of upper gastrointestinal bleeding in 168 patients with cirrhosis of the liver are examined. The source of bleeding had been determined by early endoscopy in all cases. In men under the age of 50 years, and without symptoms of liver failure, bleeding was due to ruptured gastro-oesophageal varices in 84% of cases. Severe liver failure was associated with acute lesions of gastric mucosa in many cases. No presumptive diagnosis of the source of haemorrhage could be based on the examination of other clinical data (presence of ascites, mode of presentation and pattern of bleeding, history of ulcer disease, alcoholism, and previous medication.

Intestinal and hepatic nitrogen balance in the rat after the administration of an oral protein load

The fate of a small oral dose of protein given to overnight-starved rats was studied. After 3 h, 62 per cent of the protein amino acids had been absorbed. Most of the absorbed N went into the bloodstream through the portal in the form of amino acids, but urea and ammonia were also present. About one-quarter of all absorbed N was carried as lymph amino acids. The liver was able to take all portal free ammonia and a large proportion of portal amino acids, releasing urea. The hepatic N balance was negative, indicating active proteolysis and net loss of liver protein.

Upper gastrointestinal bleeding in cirrhosis: clinical and endoscopic correlations

The clinical data of 180 episodes of upper gastrointestinal bleeding in 168 patients with cirrhosis of the liver are examined. The source of bleeding had been determined by early endoscopy in all cases. In men under the age of 50 years, and without symptoms of liver failure, bleeding was due to ruptured gastro-oesophageal varices in 84% of cases. Severe liver failure was associated with acute lesions of gastric mucosa in many cases. No presumptive diagnosis of the source of haemorrhage could be based on the examination of other clinical data (presence of ascites, mode of presentation and pattern of bleeding, history of ulcer disease, alcoholism, and previous medication.

Hepatic hemangiomas: Factors associated with T2 shine-through effect on diffusion-weighted MR sequences.

PURPOSE: To determine the frequency and factors associated with the presence of T2 shine-through effect in hepatic hemangiomas on diffusion-weighted (DW) magnetic resonance (MR) sequences. MATERIALS AND METHODS: This retrospective study was approved by institutional review board with waiver of informed consent. One hundred forty-nine consecutive patients with 388 hepatic hemangiomas who underwent a liver MR between January 2010 and November 2011 were included. MR analysis evaluated the lesion characteristics (signal intensities and enhancement patterns (classical, rapidly filling, delayed filling)), the presence of T2 shine-through effect on DW sequences (b values of 0, 150, and 600s/mm(2)), and apparent diffusion coefficient (ADC) values. Multivariate analysis was performed to study the factors associated with the T2 shine-through effect. RESULTS: T2 shine-through effect was observed in 204/388 (52.6%) of hepatic hemangiomas and in 100 (67.1%) patients. Mean ADC value of hemangiomas with T2 shine-through effect was significantly lower than hemangiomas without (2.0±0.48 vs 2.38±0.45, P<.0001). On multivariate analysis, high signal intensity on fat-suppressed T2-weighted fast spin-echo images, hemangiomas with classical or delayed enhancement, and the ADC of the liver were the only significant factors associated with T2 shine-through effect. CONCLUSION: T2 shine-through effect is commonly observed in hepatic hemangiomas and is related to hemangiomas characteristics. Radiologists should be aware of this phenomenon which could lead to misdiagnosis. Its presence should not question the diagnosis of hemangiomas when typical MR findings are found.

Lytic lesions of the femoral neck in rheumatoid arthritis simulating pigmented villonodular synovitis or malignancy

Large lytic lesions, relatively asymptomatic, involving the femoral neck and the base of the head are described in two patients suffering from a classical seropositive rheumatoid arthritis. Histological examination failed to reveal signs of malignancy, infection or pigmented villonodular synovitis. There were no rheumatoid nodules but a chronic hypertrophic villous synovitis was found. Rheumatoid synovium may invade the superior extremity of the femur; this fact is important in the differential diagnosis of destructive lesions of the femoral neck in RA.

Well, you have hepatic metastases: Use of technical language by medical students in simulated patient interviews.

OBJECTIVE: This research explored medical students' use and perception of technical language in a practical training setting to enhance skills in breaking bad news in oncology. METHODS: Terms potentially confusing to laypeople were selected from 108 videotaped interviews conducted in an undergraduate Communication Skills Training. A subset of these terms was included in a questionnaire completed by students (N=111) with the aim of gaining insight into their perceptions of different speech registers and of patient understanding. Excerpts of interviews were analyzed qualitatively to investigate students' communication strategies with respect to these technical terms. RESULTS: Fewer than half of the terms were clarified. Students checked for simulated patients' understanding of the terms palliative and metastasis/to metastasize in 22-23% of the interviews. The term ambulatory was spontaneously explained in 75% of the interviews, hepatic and metastasis/to metastasize in 22-24%. Most provided explanations were in plain language; metastasis/to metastasize and ganglion/ganglionic were among terms most frequently explained in technical language. CONCLUSION: A significant number of terms potentially unfamiliar and confusing to patients remained unclarified in training interviews conducted by senior medical students, even when they perceived the terms as technical. PRACTICE IMPLICATIONS: This exploration may offer important insights for improving future physicians' skills.

Circadian clock-coordinated hepatic lipid metabolism: only transcriptional regulation?

By regulating the metabolism of fatty acids, carbohydrates, and xenobiotic, the mammalian circadian clock plays a fundamental role on the liver physiology. At present, it is supposed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level. However, recent evidences suggest that some signaling pathways synchronized by the circadian clock can also influence metabolism at a post-transcriptional level. In this context, we have recently shown that the circadian clock synchronizes the rhythmic activation of the IRE1alpha pathway in the endoplasmic reticulum. The absence of circadian clock perturbs this secondary clock, provokes deregulation of endoplasmic reticulum-localized enzymes, and leads to impaired lipid metabolism. We will describe here the additional pathways synchronized by the clock and discussed the influence of the circadian clock-controlled feeding rhythm on them.

Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans.

OBJECTIVE: To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short-term overfeeding in healthy subjects. DESIGN AND METHODS: The analysis of the data collected in several studies in which fasting hepatic glucose production (HGP), hepatic insulin sensitivity index (HISI), and intrahepatocellular lipids (IHCL) had been measured after both 6-7 days on a weight-maintenance diet (control, C; n = 55) and 6-7 days of overfeeding with 1.5 (F1.5, n = 7), 3 (F3, n = 17), or 4 g fructose/kg/day (F4, n = 10), with 3 g glucose/kg/day (G3, n = 11), or with 30% excess energy as saturated fat (fat30%, n = 10). RESULTS: F3, F4, G3, and fat30% all significantly increased IHCL, respectively by 113 ± 86, 102 ± 115, 59 ± 92, and 90 ± 74% as compared to C (all P < 0.05). F4 and G3 increased HGP by 16 ± 10 and 8 ± 11% (both P < 0.05), and F3 and F4 significantly decreased HISI by 20 ± 22 and 19 ± 14% (both P < 0.01). In contrast, there was no significant effect of fat30% on HGP or HISI. CONCLUSIONS: Short-term overfeeding with fructose or glucose decreases hepatic insulin sensitivity and increases hepatic fat content. This indicates short-term regulation of hepatic glucose metabolism by simple carbohydrates.