- Email: [email protected]
Portal pressure lowering effects of aldosterone antagonism in postviral preascitic child a cirrhosis with small oesophageal varices is not matched with sympathoinhibition
Poster Sessions
68
and 8 controls (CON). Basal GH, IGF-1, IGFBP-3, and ALS levels were determined to verify the GH: IGF-1, GH: IGFBP-3, and GH: ALS ratios. Results: See Table. IGF-1, IGFBP-3, and ALS were significantly lower in CIR respect to CH and CON. IGF-1 and ALS were also reduced in CH respect to CON, despite similar IGFBP-3 levels. Conversely, GH was greatly increased in CIR compared to CH and CON. In CH, mean GH levels were about 1.5 times superior to CON, but the difference was not significant due to the strong variability of values in CH patients. GH: IGF1, GH: IGFBP-3, and GH: ALS ratios were significantly higher in CIR than in CH and CON. The values of such ratios clearly tended to be higher also in CH than in CON, although without statistical significance. Conclusions: Our results show that GH/IGF-1 axis is impaired also in non-cirrhotic liver disease. GH: IGF-1, GH: IGFBP-3, and GH: ALS ratios represent easy and reliable indices to determine the degree of GH-resistance in different stages of CLD.
I 217
GROWTH HORMONE-STIMULATED AND ACID LABILE SUBUNIT
INSULIN-LIKE
IN CHRONIC
FACTOR-l
LIVER DISEASE
A. Picardi’, U. Vespasiani Gentilucci’, E.M. Zardi’, F. Intelligente’, S. Manfrini3, A. Afeltra2, l? Pozzilli3. ‘Laboratory of Internal Medicine and Hepatology, 2Laboratory of Clinical Immunology, ‘Laboratory of Endocrinology, Interdisciplinary Center for Biomedical Research (CIR), University Campus Bio-Medico of Rome, Rome, Italy Background/Aims: Growth hormone (GH) -resistance complicates liver cirrhosis, with low levels of insulin-like growth factor-l (IGF-1), IGFbinding protein-3, and acid labile subunit (ALS) despite high serum GH concentrations. A GH-test has been already proposed to define liver function and prognosis. We aimed to compare liver response to short term GH challenge among patients with liver cirrhosis and with non-cirrhotic chronic liver disease (CLD). Methods: 17 patients with chronic hepatitis (CH), and 19 patients with cirrhosis (CIR) were studied and compared with 11 controls (CON). Patients received 0.14 UVKg of GH SC, and blood was drawn before and 24 hours after GH injection to determine IGF-1 and ALS levels. Results: Basal IGF-1 resulted significantly lower in CIR respect to CH (.5.3&5.8 vs 14.9&10.5 nmol/l, p
increase in collagen synthesis is the hallmark of the disease. In rat liver, halofuginone prevented dimethylnitrosamine (DMN) and thioacetamide (TAA) -induced fibrosis and was responsible for both resolution of advanced fibrosis and increased cirrhotic liver regeneration. In this study, liver fibrosis was induced in rats by intraperitoneal administration of TAA (200 mg/kg twice weekly for 1,2 and 4 weeks), and halofuginone was given in the diet (5 ppm). Using Atlas and chip microarray techniques in viva we identified A- genes involved in the progression of TM-induced liver fibrosis and B- genes responsible for the halofuginone-dependent prevention of fibrosis. Halofuginone’s safety, tolerability and pharmacokinetic profile were examined in single ascending doses in 26 healthy volunteers. The drug was found safe and well-tolerated with no clinically significant abnormal values reported for the safety parameters assessed up to 0.5 mg. At this concentration, plasma levels exceeded the therapeutic levels attained in animal models. Halofuginone given orally was readily bioavailable, rapidly absorbed and the t 112 was approximately 24 h. In summary, the gene profile of halofuginone action in preventing fibrosis was revealed. Halofuginone was found to be well-tolerated and surpassed predicted therapeutic levels while maintaining a good safety profile. Halofuginone may become a novel and promising therapy for liver fibrosis.
I
219
PORTAL PRESSURE ALDOSTERONE
CHILD A CIRRHOSIS IS NOT MATCHED
218
HALOFUGINONEMECHANISM
A NEW THERAPY
FOR LIVER FIBROSIS:
OF ACTION AND PHASE I STUDY
Y. Gnainsky’,
G. Spira2, R. Bruck3, A. Nagler4, D. Snyder’, Y. Yarkoni’, T.A. Libermann6 M. Pines’. ‘Institute OfAnimal Science, Volcani Centec Bet Dagakslke Faculty Of Medicine, Technion, Haifa, Israel; ‘Department Of Gastroenterology, Wolfson Medical Centec Holon, Israel; 4Department Of Bone Marrow Transplantation, Tel Hashomes Israel; ‘Collgard Biopharmaceuticals LTD, Israel; 6Beth Israel Deaconess Medical Centec Boston, USA
Hepatic Fibrosis, which is characterised by an immense increase in collagen synthesis, represents the response of the liver to diverse insults causing significant morbidity and mortality. Halofuginone is a well-known inhibitor of collagen type I synthesis as demonstrated in multiple studies in which
EFFECTS
OF
IN POSTVIRAL
PREASCITIC
WITH SMALL OESOPHAGEAL
VARICES
WITH SYMPATHOINHIBITION
M. Pozzi’, G. Grassi’, L. Ratti’, G. Favini2, E. Redaelli’, F. Quarti Trevano’, A. Facchini’, A. Redaelli’, G. Poli’, S. Foresti’, G. Mancia’. ‘Department Of Internal Medicine, Chair Of Internal Medicine; 2Department Of Radiology, San Gerard0 Hospital Monza, University Of Milan0 Bicocca, Monza, Italy A clinically significant Hepatic Venous Pressure Gradient (HVPG > 10 mmHg) can already be detected in Child A cirrhotics with Fl varices. Treatment is recommended for the primary prophilaxis of variceal bleeding only when varices of greater size are identified, subjects with Fl varices actually being in a “therapeutic limbo”. However even in this condition neurohumoral overactivity can be detected by the measurement of sympathetic neural discharge by microneurography (Muscle Sympathetic Nerve Activity-MSNA), a reliable marker of SNS overactivity. Aim: to investigate the mid-term effects of aldosterone antagonism by KCanrenoate on MSNA and HVPG in Child A cirrhotics with Fl varices and baseline HVPG > 10 mmHg. Methods: 19 histology proven postviral Child A cirrhotics underwent recording of efferent postganglionic MSNA obtained from a peroneal nerve. MSNA and HVPG were repeated after 6 months of 200 mg KCanrenoate (group A) and after no treatment (group B) in the 16 patients who have already completed the study protocol (9 and 7 respectively).
Normal values
BFdine Group A
I
LOWERING
ANTAGONISM
P
Group B
Total MSNA (< 35 bursts/m) 46.3&5.36 43.X&4.5 NS MSNA (< 40 bl 100 heartbeats) 61.X&5.13 61.X&4.1 NS HVPG (mm Hg) 13.X&0.86 14.1&1.4 NS
After 6 months
P
K-Canrenoate (A) no therapy (B) 44.2&6.X
45.3&2.X
NS
58.2xJ.7 12.3&0.X
67.OXJ.6 15.x*1.4
NS 0.05
Results and Conclusions: In Child A cirrhosis with Fl varices MSNA is already increased. Six months treatment with 200 mg K-Canrenoate reduces HVPG (6 out of 9 pts) with no changes of the MSNA: in only one patient a slight reduction of HVPG was observed after no treatment. Preliminary findings of this ongoing study do not allow definite conclusions. Nevertheless the potential role of aldosterone antagonism in decreasing HVPG should be more extensively investigated along with the observed lack of effects on the SNS overactivity.
68
and 8 controls (CON). Basal GH, IGF-1, IGFBP-3, and ALS levels were determined to verify the GH: IGF-1, GH: IGFBP-3, and GH: ALS ratios. Results: See Table. IGF-1, IGFBP-3, and ALS were significantly lower in CIR respect to CH and CON. IGF-1 and ALS were also reduced in CH respect to CON, despite similar IGFBP-3 levels. Conversely, GH was greatly increased in CIR compared to CH and CON. In CH, mean GH levels were about 1.5 times superior to CON, but the difference was not significant due to the strong variability of values in CH patients. GH: IGF1, GH: IGFBP-3, and GH: ALS ratios were significantly higher in CIR than in CH and CON. The values of such ratios clearly tended to be higher also in CH than in CON, although without statistical significance. Conclusions: Our results show that GH/IGF-1 axis is impaired also in non-cirrhotic liver disease. GH: IGF-1, GH: IGFBP-3, and GH: ALS ratios represent easy and reliable indices to determine the degree of GH-resistance in different stages of CLD.
I 217
GROWTH HORMONE-STIMULATED AND ACID LABILE SUBUNIT
INSULIN-LIKE
IN CHRONIC
FACTOR-l
LIVER DISEASE
A. Picardi’, U. Vespasiani Gentilucci’, E.M. Zardi’, F. Intelligente’, S. Manfrini3, A. Afeltra2, l? Pozzilli3. ‘Laboratory of Internal Medicine and Hepatology, 2Laboratory of Clinical Immunology, ‘Laboratory of Endocrinology, Interdisciplinary Center for Biomedical Research (CIR), University Campus Bio-Medico of Rome, Rome, Italy Background/Aims: Growth hormone (GH) -resistance complicates liver cirrhosis, with low levels of insulin-like growth factor-l (IGF-1), IGFbinding protein-3, and acid labile subunit (ALS) despite high serum GH concentrations. A GH-test has been already proposed to define liver function and prognosis. We aimed to compare liver response to short term GH challenge among patients with liver cirrhosis and with non-cirrhotic chronic liver disease (CLD). Methods: 17 patients with chronic hepatitis (CH), and 19 patients with cirrhosis (CIR) were studied and compared with 11 controls (CON). Patients received 0.14 UVKg of GH SC, and blood was drawn before and 24 hours after GH injection to determine IGF-1 and ALS levels. Results: Basal IGF-1 resulted significantly lower in CIR respect to CH (.5.3&5.8 vs 14.9&10.5 nmol/l, p
increase in collagen synthesis is the hallmark of the disease. In rat liver, halofuginone prevented dimethylnitrosamine (DMN) and thioacetamide (TAA) -induced fibrosis and was responsible for both resolution of advanced fibrosis and increased cirrhotic liver regeneration. In this study, liver fibrosis was induced in rats by intraperitoneal administration of TAA (200 mg/kg twice weekly for 1,2 and 4 weeks), and halofuginone was given in the diet (5 ppm). Using Atlas and chip microarray techniques in viva we identified A- genes involved in the progression of TM-induced liver fibrosis and B- genes responsible for the halofuginone-dependent prevention of fibrosis. Halofuginone’s safety, tolerability and pharmacokinetic profile were examined in single ascending doses in 26 healthy volunteers. The drug was found safe and well-tolerated with no clinically significant abnormal values reported for the safety parameters assessed up to 0.5 mg. At this concentration, plasma levels exceeded the therapeutic levels attained in animal models. Halofuginone given orally was readily bioavailable, rapidly absorbed and the t 112 was approximately 24 h. In summary, the gene profile of halofuginone action in preventing fibrosis was revealed. Halofuginone was found to be well-tolerated and surpassed predicted therapeutic levels while maintaining a good safety profile. Halofuginone may become a novel and promising therapy for liver fibrosis.
I
219
PORTAL PRESSURE ALDOSTERONE
CHILD A CIRRHOSIS IS NOT MATCHED
218
HALOFUGINONEMECHANISM
A NEW THERAPY
FOR LIVER FIBROSIS:
OF ACTION AND PHASE I STUDY
Y. Gnainsky’,
G. Spira2, R. Bruck3, A. Nagler4, D. Snyder’, Y. Yarkoni’, T.A. Libermann6 M. Pines’. ‘Institute OfAnimal Science, Volcani Centec Bet Dagakslke Faculty Of Medicine, Technion, Haifa, Israel; ‘Department Of Gastroenterology, Wolfson Medical Centec Holon, Israel; 4Department Of Bone Marrow Transplantation, Tel Hashomes Israel; ‘Collgard Biopharmaceuticals LTD, Israel; 6Beth Israel Deaconess Medical Centec Boston, USA
Hepatic Fibrosis, which is characterised by an immense increase in collagen synthesis, represents the response of the liver to diverse insults causing significant morbidity and mortality. Halofuginone is a well-known inhibitor of collagen type I synthesis as demonstrated in multiple studies in which
EFFECTS
OF
IN POSTVIRAL
PREASCITIC
WITH SMALL OESOPHAGEAL
VARICES
WITH SYMPATHOINHIBITION
M. Pozzi’, G. Grassi’, L. Ratti’, G. Favini2, E. Redaelli’, F. Quarti Trevano’, A. Facchini’, A. Redaelli’, G. Poli’, S. Foresti’, G. Mancia’. ‘Department Of Internal Medicine, Chair Of Internal Medicine; 2Department Of Radiology, San Gerard0 Hospital Monza, University Of Milan0 Bicocca, Monza, Italy A clinically significant Hepatic Venous Pressure Gradient (HVPG > 10 mmHg) can already be detected in Child A cirrhotics with Fl varices. Treatment is recommended for the primary prophilaxis of variceal bleeding only when varices of greater size are identified, subjects with Fl varices actually being in a “therapeutic limbo”. However even in this condition neurohumoral overactivity can be detected by the measurement of sympathetic neural discharge by microneurography (Muscle Sympathetic Nerve Activity-MSNA), a reliable marker of SNS overactivity. Aim: to investigate the mid-term effects of aldosterone antagonism by KCanrenoate on MSNA and HVPG in Child A cirrhotics with Fl varices and baseline HVPG > 10 mmHg. Methods: 19 histology proven postviral Child A cirrhotics underwent recording of efferent postganglionic MSNA obtained from a peroneal nerve. MSNA and HVPG were repeated after 6 months of 200 mg KCanrenoate (group A) and after no treatment (group B) in the 16 patients who have already completed the study protocol (9 and 7 respectively).
Normal values
BFdine Group A
I
LOWERING
ANTAGONISM
P
Group B
Total MSNA (< 35 bursts/m) 46.3&5.36 43.X&4.5 NS MSNA (< 40 bl 100 heartbeats) 61.X&5.13 61.X&4.1 NS HVPG (mm Hg) 13.X&0.86 14.1&1.4 NS
After 6 months
P
K-Canrenoate (A) no therapy (B) 44.2&6.X
45.3&2.X
NS
58.2xJ.7 12.3&0.X
67.OXJ.6 15.x*1.4
NS 0.05
Results and Conclusions: In Child A cirrhosis with Fl varices MSNA is already increased. Six months treatment with 200 mg K-Canrenoate reduces HVPG (6 out of 9 pts) with no changes of the MSNA: in only one patient a slight reduction of HVPG was observed after no treatment. Preliminary findings of this ongoing study do not allow definite conclusions. Nevertheless the potential role of aldosterone antagonism in decreasing HVPG should be more extensively investigated along with the observed lack of effects on the SNS overactivity.