Carolina Tiani

University of Bologna

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Annalisa Berzigotti

University Hospital of Bern

Donatella Magalotti

Azienda USL di Bologna

P. Zappoli

University of Bologna

Marco Zoli

University of Bologna

Jaime Bosch

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Valentina A. Rossi

University Hospital of Zurich

Nicola Castaldini

Maria Cecilia Hospital

Pietro Andreoné

University of Modena and Reggio Emilia

Mercedes Fernández

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Ester García-Pras

Universitat de Barcelona

Cooperative Institutions

University of Bologna

Policlinico S.Orsola-Malpighi

Ibero American University

Azienda USL di Bologna

University of Padua

Istituti di Ricovero e Cura a Carattere Scientifico

University of Modena and Reggio Emilia

Medica (Italy)

Universitat de Barcelona

University College London

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The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats

Journal of Cellular and Molecular Medicine (2008)

Marc Mejías Ester García-Pras Carolina Tiani Jaime Bosch Mercedes Fernández

Abstract Background: Angiogenesis is an important determinant of the pathophysiology of portal hypertension contributing to the formation of portosystemic collateral vessels and the hyperdynamic splanchnic circulation associated to this syndrome. Somatostatin and its analogues, like octreotide, have been shown to be powerful inhibitors of experimental angiogenesis. Aim: To determine whether octreotide has angioinhibitory effects in portal hypertensive rats. Methods: Partial portal vein‐ligated (PPVL) rats were treated with octreotide or vehicle during 4 or 7 days. Splanchnic neovascularization and VEGF expression were determined by histological analysis and western blotting. Expression of the somatostatin receptor subtype 2 (SSTR2), which mediates the anti‐angiogenic effects of octreotide, was also analyzed. Formation of portosystemic collaterals (radioactive microspheres) and hemodynamic parameters were also measured. Results: Octreotide treatment during 4 days markedly and significantly decreased splanchnic neovascularization, VEGF expression by 63% and portal pressure by 15%, whereas portosystemic collateralization and splanchnic blood flow were not modified. After 1 week of octreotide injection, portal pressure was reduced by 20%, but inhibition of angiogenesis escaped from octreotide therapy, a phenomenon that could be related to the finding that expression of SSTR2 receptor decreased progressively (up to 78% reduction) during the evolution of portal hypertension. Conclusion: This study provides the first experimental evidence showing that octreotide may be an effective anti‐angiogenic therapy early after induction of portal hypertension, but not in advanced stages most likely due to SSTR2 down‐regulation during the progression of portal hypertension in rats. These findings shed light on new mechanisms of action of octreotide in portal hypertension.

Somatostatin Analogue

10.1111/j.1582-4934.2008.00218.x

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Dati preliminari dello studio multicentrico caso-controllo "Grave danno epatico acuto indotto da farmaci"

Carolina Tiani

Il danno epatico indotto dall'assunzione di farmaci viene comunemente indicato con il termine inglese DILI (Drug-Induced Liver Injury). Il paracetamolo rappresenta la causa piu comune di DILI, seguito da antibiotici, FANS e farmaci antitubercolari. In particolare, i FANS sono una delle classi di farmaci maggiormente impiegate in terapia. Numerosi case report descrivono pazienti che hanno sviluppato danno epatico fatale durante il trattamento con FANS; molti di questi farmaci sono stati ritirati dal commercio in seguito a gravi reazioni avverse a carico del fegato. L'ultimo segnale di epatotossicita indotto da FANS e associato alla nimesulide; in alcuni paesi europei come la Finlandia, la Spagna e l'Irlanda, la nimesulide e stata sospesa dalla commercializzazione perche associata ad un'alta frequenza di epatotossicita. Sulla base dei dati disponibili fino a questo momento, l'Agenzia Europea dei Medicinali (EMA) ha recentemente concluso che i benefici del farmaco superano i rischi; un possibile aumento del rischio di epatotossicita associato a nimesulide rimane tuttavia una discussione aperta di cui ancora molto si dibatte. Tra le altre classi di farmaci che possono causare danno epatico acuto la cui incidenza tuttavia non e sempre ben definita sono gli antibiotici, quali amoxicillina e macrolidi, le statine e gli antidepressivi.Obiettivo dello studio e stato quello di determinare il rischio relativo di danno epatico indotto da farmaci con una prevalenza d'uso nella popolazione italiana maggiore o uguale al 6%. E’ stato disegnato uno studio caso controllo sviluppato intervistando pazienti ricoverati in reparti di diversi ospedali d’Italia. Il nostro studio ha messo in evidenza che il danno epatico da farmaci riguarda numerose classi farmacologiche e che la segnalazione di tali reazioni risulta essere statisticamente significativa per numerosi principi attivi. I dati preliminari hanno mostrato un valore di odds ratio significativo statisticamente per la nimesulide, i FANS, alcuni antibiotici come i macrolidi e il paracetamolo.

Nimesulide

10.6092/unibo/amsdottorato/6387

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Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats

Hepatology (2008)

Marc Mejías Ester García-Pras Carolina Tiani Rosa Miquel Jaime Bosch

Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs.Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.

Hyperdynamic circulation

Collateral circulation

Splanchnic Circulation

10.1002/hep.22758

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Contents

Digestive and Liver Disease (2008)

S Cucchiara Ann C. Noble R Baldassano Petar Mamula Athos Bousvaros

10.1016/s1590-8658(07)00654-8

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673 Prevalence and factors associated with fatty liver in a geriatric population: Results from the pianoro study

Journal of Hepatology (2006)

Annalisa Berzigotti Donatella Magalotti Carolina Tiani Susanna Dapporto Cosimo Ludovico

10.1016/s0168-8278(06)80673-2

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Age Dependency of Regional Impedance Indices Regardless of Clinical Stage in Patients with Cirrhosis of the Liver

Ultraschall in der Medizin - European Journal of Ultrasound (2009)

Annalisa Berzigotti Nicola Castaldini Valentina A. Rossi Donatella Magalotti Carolina Tiani

To prospectively assess if ageing itself induces modifications of the impedance indices (resistance and pulsatility indexes) of hepatic, splenic, superior mesenteric and renal arteries in patients with liver cirrhosis.78 consecutive patients with cirrhosis (41 males, 37 females, Child-Pugh score 7 [range 5 - 12]) were studied by colour-Doppler ultrasound. The resistance index (RI) and pulsatility index (PI) were determined in the main hepatic artery, intraparenchymal branches of hepatic, splenic, and renal arteries, and superior mesenteric artery; clinical data were simultaneously collected. Logistic regression analysis was performed to assess the relative impact of age, severity of liver disease and other relevant variables on the increase of impedance indices. Linear regression analysis was used to identify a coefficient to adjust RIs and PIs to age.Resistance and pulsatility indices of all the vessels studied except of the superior mesenteric artery showed a direct correlation with age (e. g. splenic artery RI: R = 0.520, p < 0.0001), and correlated most strongly with Child-Pugh score (e. g. right renal artery PI: R = 0.462, p < 0.0001). Age was associated independently with increased PI and RI in hepatic, splenic and renal arterial districts. In these vessels, the RI threshold of normality can be adjusted to the decade of age adding a correction of 0.03.Ageing itself induces an increase of hepatic, splenic and renal impedance indices in cirrhotic patients. The threshold of normality for these indices in cirrhosis should be adjusted according to the patients' age.

10.1055/s-2008-1027742

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New abdominal collaterals at ultrasound: A clue of progression of portal hypertension

Digestive and Liver Disease (2007)

Annalisa Berzigotti Carlo Merkel Donatella Magalotti Carolina Tiani S. Gaiani

Abdominal ultrasonography

Abdominal ultrasound

10.1016/j.dld.2007.08.011

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Citations (38)

In portal hypertensive cirrhotic patients abdominal porto-systemic collaterals at ultrasound identify a group of patients at high risk of death