Eric Vuillemin

Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis and/or portal hypertension

BACKGROUND/AIMS To assess the effects of the early and chronic administration of losartan--a specific angiotensin II receptor antagonist--in the prevention of hepatic fibrosis and portal hypertension. METHODS/RESULTS (1) In CCl(4) rats, losartan at 5 and 10 mg/kg per day significantly decreased portal pressure (-11, -18%, respectively), splenorenal shunt blood flow (-60, -80%) and liver fibrosis (liver hydroxyproline and area of fibrosis) without significant changes in mortality and mean arterial pressure (MAP). (2) In bile duct ligated (BDL) rats, losartan at 5 mg/kg per day significantly decreased portal pressure (-14%), splenorenal shunt blood flow (-70%) and liver fibrosis. Losartan at 10 mg/kg per day significantly worsened liver and renal functions, mortality and liver fibrosis, without significant changes in portal pressure and splenorenal shunt blood flow. Losartan at 5 and 10 mg/kg per day significantly decreased MAP (-24, -30%). (3) In portal vein ligated (PVL) rats, losartan significantly decreased MAP (-12%) but did not change portal pressure or splenorenal shunt blood flow. CONCLUSIONS In BDL and CCl(4) rats, losartan has beneficial effects on splanchnic hemodynamics and liver fibrosis. Losartan might decrease hepatic resistances in fibrotic liver. Losartan decreased MAP except in CCl(4) rats. Higher dosage of losartan had deleterious effects in BDL rats.

Prothrombin index is an indirect marker of severe liver fibrosis

Objective The non-invasive diagnosis of liver fibrosis is based mainly on biochemical markers. The main aim was to validate whether the prothrombin index is an indirect marker of the severity of liver fibrosis. Patients and methods The predictive value of the prothrombin index for liver fibrosis was first assessed in 243 patients with chronic liver disease, then validated in 193 other patients with chronic liver disease. The reproducibility of measurement of the prothrombin index in different laboratories was evaluated in 82 other patients. Results In the first group, the prothrombin index was predicted accurately by serum hyaluronate (R2 = 0.67 at the first step by multiple regression). The relationship between the prothrombin index and the area of fibrosis was not influenced significantly by non-fibrotic pathological lesions. The prothrombin index began to decrease when the Metavir fibrosis score was 2 versus 3 for albumin. In the second group, the prothrombin index and the histological fibrosis score were well correlated (r =− 0.70, P < 10–4). Prothrombin index ⩽80% or ⩽70% diagnosed severe fibrosis or cirrhosis, respectively, and prothrombin index ⩾105% or ⩾100% excluded a diagnosis of severe fibrosis or cirrhosis, respectively, at the 95% probability level. The prothrombin indices measured in different laboratories were similar (78 ± 18%v. 78 ± 14%) and well correlated (r = 0.91, P < 10–4). Conclusions The prothrombin index was well correlated with pathological liver fibrosis score, had a high diagnostic accuracy for severe fibrosis or cirrhosis especially due to alcohol, and was not influenced by other pathological lesions. The prothrombin index was reproducible. Thus, the prothrombin index expressed as a percentage is an accurate, reproducible, inexpensive and easily available marker of severe liver fibrosis.

Hepatic hyper-vitaminosis A: importance of retinyl ester level determination.

&NA; We report the case of a 32‐year‐old man with portal hypertension without cirrhosis due to chronic vitamin A intoxication. Portal hypertension revealed by oesophageal varice rupture progressively worsened and ascites occurred 5 years after the patient stopped vitamin A intake. Initially, serum retinyl palmitate concentration was increased whereas serum retinol concentration was normal. There was no hepatic fibrosis on light microscopic examination of liver biopsy specimens. Five years after the patient stopped excessive vitamin A intake, serum retinol and retinol‐binding protein concentrations were below the normal range even though there was an increased hepatic retinyl ester content. This was attributed to the late development of peri‐sinusoidal fibrosis. This case mainly shows the importance of retinyl ester level determination: serum retinyl palmitate should be measured immediately after intoxication and hepatic retinyl esters should be measured initially and particularly later. Indeed, later serum and hepatic retinol levels in chronic hyper‐vitaminosis A may be normal and lead to under‐estimation of liver vitamin A overload. Eur J Gastroenterol Hepatol 12:361‐364

Spleno-renal shunt blood flow is an accurate index of collateral circulation in different models of portal hypertension and after pharmacological changes in rats

BACKGROUND/AIMS Recently, we developed a new method to measure collateral blood flow in rats: splenorenal shunt (SRS) blood flow (BF). The aims were to evaluate the reproducibility of SRSBF measurement in different models of portal hypertension, and to investigate the ability of SRSBF to disclose pharmacological changes. METHODS Hemodynamics were determined in anesthetized rats with secondary biliary, CCl4 or DMNA cirrhosis and portal vein ligation (PVL) under baseline and pharmacological (octreotide, vapreotide) conditions. The main measurements performed were: SRSBF by the transit time ultrasound (TTU) method and % portosystemic shunts (PSS) by the microsphere method. RESULTS SRSBF was 6 to 10 times higher in portal hypertensive rats and was similar in the different models of cirrhosis but was higher in portal vein ligated rats than in cirrhotic rats (1.1+/-0.7 vs 0.6+/-0.7 ml x min(-1) x 100 g(-1), p=0.01). SRSBF was correlated with mesenteric %PSS (r=0.61, p<0.01), splenic %PSS (r=0.54, p<0.05), portal pressure (r= 0.32, p<0.05) and the area of liver fibrosis (r=0.33, p<0.05). Octreotide significantly decreased SRSBF (-23+/-20%, p<0.01 vs placebo: -6+/-8%, NS). Vapreotide significantly decreased SRSBF but not mesenteric or splenic %PSS compared to placebo. The variations in SRSBF (-26+/-32%) and in splenic %PSS (0+/-15%) with vapreotide were significantly different (p<0.05) and not correlated (r=-0.1, NS). CONCLUSIONS Determination of SRSBF by TTU is an accurate way to measure collateral blood flow in different models of intra- and extra-hepatic portal hypertension in rats. Its sensitivity provides accurate measurement of pharmacological changes, unlike the traditional estimation of %PSS by the microsphere method.

Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis.

The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 μg/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution–TTU method. Acute administration of vapreotide significantly decreased SRS BF (−17.3 ± 19 vs −1.1 ± 14%, P < 0.05) and portal pressure (−8 ± 9 vs 0 ± 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 ± 1.5 vs 1.2 ± 1.0 ml/min, P < 0.05) and cardiac index (50 ± 15 vs 33 ± 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.

Révélation d'une tumeur stromale mésentérique par une complication de la coloscopie

Un homme de 60 ans était hospitalisé en août 2002 dans notre unité pour des douleurs abdominales associées à une hyperthermie. Il était traité depuis plusieurs années pour un diabète de type 2 correctement équilibré et n’avait pas d’autre antécédent. Deux semaines plus tôt une coloscopie de dépistage avait été réalisée sans difficulté technique permettant la résection d’un polype pédiculé de 20 mm du colon transverse. Aucune complication immédiate n’était notée et le malade était rentré à son domicile quelques heures plus tard. L’examen histologique du polype montrait un adénome tubulo-villeux. Les jours suivant la coloscopie, le malade avait présenté des douleurs abdominales et une distension abdominale d’installation progressive. Vingt-quatre heures avant l’hospitalisation, une hyperthermie à 39°5 C avec frissons était apparue. La palpation abdominale révélait une masse arrondie et tendue s’étendant de la région péri-ombilicale à la région sus-pubienne. Le toucher rectal était normal. Le bilan biologique montrait une anémie (hémoglobine : 10,7 g/dL contre 15,8 g/dL en mars 2002) normocytaire (VGM = 88) et un syndrome inflammatoire (protéine C réactive : 152 mg/L). L’échographie et le scanner abdominaux confirmaient la présence d’une volumineuse masse de 20 cm de contenu liquidien située dans le mésentère, hypodense, avec une prise de contraste au temps artériel au contact du mésentère (figure 1). Il n’était pas observé d’adénopathie. Une ponction guidée sous contrôle scannographique permettait de prélever 2,7 L de liquide sanglant et purulent. L’examen bactériologique et anatomo-pathologique de ce liquide montrait la présence de Streptococcus Anginosus sans cellules néoplasiques. Le 13 août une laparoscopie était réalisée confirmant la présence d’une volumineuse masse mésentérique avec une paroi épaisse. Son exérèse nécessitait une conversion en laparotomie avec résection cunéiforme de l’intestin grêle. L’examen anatomo-pathologique montrait une tumeur mésenchymateuse d’aspect pseudo-kystique, nécrotique et très hémorragique pesant 600 g et mesurant 16 cm dans son plus grand axe, avec une paroi de 3 cm. L’indice mitotique était modéré (score 2) et l’immuno-marquage montrait qu’il s’agissait d’une tumeur stromale CD 117+. La résection chirugicale étant considérée comme complète, aucun traitement complémentaire n’était proposé. En mars 2004, le malade était en bon état général et le scanner abdominal ne montrait pas de récidive.

Renal and hemodynamic effects of β blockers and nitrates in cirrhosis

Effects of Rblockers and nitrates on arterial pressure and renal function are controversial in cirrhosis. Therefore, we studied these factors in 198 consecutive patients divided into 2 groups: Grl: treated patients (n=129); Gr2: apparied untreated patients (n=69). The predictive value of 31 baseline variables and 30 follow-up (FU) variables for the occurence of a decrease in arterial pressure (DAP: SAP l20 ltmol/I) was studied. Results: in Grl, 82% of patients were given propranolol. FU was similar in Grl (25~h24 mo) and Gr2 (30&32 mo, NS). Side effect occurence was 34% (24% were DAP or RD according to the clinician). However, the frequences of DAP and RD were not significantly different between Grl and Gr2. In Grl, independent predictive variables (Cox model) of DAP were: MAP (P=O.O3), and Child-Pugh score (P=O.O7) and that of RD were: body temperature (P=O.OOOl), baseline creatinine (P=O.OOl), diuretics (P=O.OOl), prothrombin index (P=O.O2), serum Na (P=O.O5) and BUN (P=O.O7). In Gr 1+2, the predictive variables were a) for DAP: FU decrease in hemoglobin (P=O.O04) and in body temperature (P=O.O4), baseline serum Na (P=O.O6) and treatment (P=O.O8); b) for RD: BUN (P=O.OOOl), body weight (P=O.O5), FU decrease in prothrombin index (P=O.Ol), diuretics (P=O.O6), and age (P=O.l). Conclusions: Clinicians overestimate the frequence of Bblocker side effects. Bblockers do not alter renal function but could decrease blood pressure. Besides, anemia and infection predict DAP; BUN, prothrombin, diuretics, weight, Na, age and infection predict RD. Ccl,-INDUCED LIVER INFLAMMATION AND NECROSIS IN