Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis.

BACKGROUND/AIMS: In patients with cirrhosis, decreased renal water excretion is a common complication. Niravoline (RU51599), a kappa-opioid receptor agonist, has been shown to induce an aquaretic response. The aim of this study was to evaluate the aquaretic effect and tolerance of niravoline in patients with cirrhosis. METHODS: Biochemical tests and hemodynamic values were determined before and 1, 2, 3 and 24 h after niravoline administration at doses ranging from 0.5 to 2 mg iv in 18 patients with cirrhosis. RESULTS: Diuresis significantly increased in the first hour from 64+/-9 to 146+/-31 ml/h, and returned to basal values after 3 h. Free water clearance also significantly increased, reaching the positive range at 1 h. Plasma osmolality significantly decreased at 2 h (from 290+/-4 to 286+/-4 mOsm/kg). Plasma sodium concentrations increased significantly at 3 h (from 133+/-1 to 134+/-1 mEq/l). Heart rate and arterial pressure did not change. The highest doses (1.5 mg or 2 mg) induced personality disorders and mild confusion within 2 h. These effects reversed completely within 8 h. CONCLUSION: This study shows that niravoline administration induces an aquaretic response and is well tolerated, at moderate doses, in patients with cirrhosis. Thus, moderate doses of niravoline may be useful for treating patients with cirrhosis and water retention.

Doppler ultrasonographic evaluation of the early changes in renal resistive index in cirrhotic patients undergoing liver transplantation.

Renal vasoconstriction commonly occurs in decompensated liver cirrhosis and is entirely reversible after hepatic transplantation. In this study we evaluated by Doppler ultrasonography the changes of renal vascular resistance occurring during the first month after transplantation. In 16 cirrhotic patients the intrarenal resistive index at the level of interlobar arteries and the blood urea nitrogen and serum creatinine levels were measured before (range, 1 to 34 days) and after transplantation (days 1, 3, 7, 14, 30). Before transplantation the median resistive index value was 0.69 (95% CI, 0.65 to 0.71) and eight of 16 patients showed abnormal values (0.70 or more). After transplantation, the median resistive index was significantly decreased on all the evaluation days, and no patient had abnormal values on posttransplantation day 7. No significant correlation was found between resistive index and serum creatinine or blood urea nitrogen levels. Doppler ultrasonography is a simple tool to evaluate the recovery of normal intrarenal arterial resistance levels after liver transplantation. One week appears to be the optimal timing to evaluate the renal resistive index in the posttransplantation period.

Relation between severity of liver disease and renal oxygen consumption in patients with cirrhosis.

BACKGROUND: Worsening cirrhosis may lead to increased renal O2 metabolism caused by activation of neurohumoral antinatriuretic substances. AIMS: To evaluate the relation between the severity of liver disease, sodium excretion, and neurohumoral antinatriuretic substances on the one hand and renal O2 metabolism on the other in patients with cirrhosis. METHODS: Renal O2 consumption and haemodynamics as well as plasma concentrations of noradrenaline, renin, and aldosterone were measured. Investigations were performed in 14 patients with Pugh's grade A, 43 with grade B, and 29 with grade C liver disease. RESULTS: Renal O2 consumption significantly increased with the severity of cirrhosis (grade A, 8.9 (1.6); grade B, 15.5 (1.3); grade C, 18.0 (1.5) ml/min/m2). Plasma concentrations of noradrenaline, renin, and aldosterone significantly increased while mean arterial presssure and systemic vascular resistance significantly decreased with the severity of the disease. A significant inverse correlation was found between renal O2 consumption and sodium excretion. A significant direct correlation was found between plasma levels of noradrenaline and aldosterone on the one hand and renal O2 consumption on the other. Renal blood flow and the glomerular filtration rate did not differ significantly between patients with grade C and grade A or B disease. CONCLUSIONS: This study shows for the first time that, in patients with cirrhosis, worsening of the disease is associated with an increase in renal O2 consumption. The results suggest that increased renal O2 consumption is due to renal tubular sodium retention caused by increased levels of neurohumoral antinatriuretic substances. This neurohumoral activation is related to cirrhosis induced vasodilation.

Protein kinase C alterations in aortic vascular smooth muscle cells from rats with cirrhosis.

BACKGROUND/AIMS: Alterations in signal transduction in vascular smooth muscle cells may contribute to vascular hyporeactivity in cirrhosis. Protein kinase C plays a role in vascular cell contraction by modifying contractile proteins and intracellular [Ca2+] homeostasis. The aim of this study was to examine the vascular reactivity and expression of protein kinase Calpha in aortae from rats with cirrhosis. METHODS: The contractile response to phorbol ester, a protein kinase C activator, was evaluated in endothelium-denuded aortic rings from normal and cirrhotic rats. Protein kinase Calpha expression was determined by Western blot analysis. RESULTS: Maximal contraction was significantly less marked in cirrhotic (1.24+/-0.24 g) than in control (3.43+/-0.27 g) aortae. Phorbol myristate-acetate-induced contraction was dependent on extracellular [Ca2+] concentrations, as shown by a reduction in maximal contraction when control and cirrhotic aortic rings were exposed to a Ca2+-free medium. Increasing the intracellular [Ca2+], by incubation with a Ca2+ ionophore, significantly increased the maximal contraction induced by phorbol myristate-acetate in cirrhotic but not in control rat aortae. Protein kinase Calpha expression was significantly lower in aortae in cirrhotic than in control rats. CONCLUSION: These results confirm alterations in protein kinase C in aortae from cirrhotic rats.

Responsiveness to growth factors in aortic vascular smooth muscle cells from rats with cirrhosis.

Hemodynamic changes in cirrhosis may be associated with alterations in aortic vascular smooth muscle cell (AVSMC) function. The present study compared the proliferative response to serum and growth factors in cirrhotic and control AVSMC. Serum from cirrhotic rats, cirrhotic cell lysates, and the conditioned medium of cultured cirrhotic AVSMC induced an increase in [3H]thymidine incorporation in control but not in cirrhotic AVSMC. Platelet-derived growth factor-beta (PDGF-BB) induced a greater increase in [3H]thymidine incorporation in cirrhotic than in control cells. [3H]thymidine incorporation induced by cirrhotic conditioned medium was blocked by anti-PDGF antibody. Immunoblot studies showed that the anti-PDGF antibody recognized a 30-kDa protein in the conditioned medium of cirrhotic AVSMC culture, a protein corresponding to PDGF. Binding studies of PDGF-BB indicated a twofold increase in receptor density in cirrhotic AVSMC with no alteration in affinity for PDGF-BB. We conclude that an increased responsiveness of cirrhotic AVSMC to the PDGF could contribute to alterations in AVSMC and muscle cell tone that may play a role in the hemodynamic changes in cirrhosis.

Altered growth and lack of responsiveness to angiotensin II in aortic vascular smooth muscle cells from cirrhotic rats.

BACKGROUND & AIMS: In cirrhosis, increased amounts of circulating hormones such as angiotensin II may induce vascular tone changes and alter vascular smooth muscle cell (VSMC) function and growth. The aim of this study was to investigate the growth of aortic VSMCs from cirrhotic rats with or without the addition of angiotensin II and to determine whether angiotensin II binding was preserved in cirrhotic VSMCs. METHODS: Cirrhosis was induced by bile duct ligation. Cell growth was studied in cultured aortic VSMCs at passage levels between 4 and 16 by determining cell number and protein synthesis. RESULTS: Proliferation rates of cirrhotic VSMCs were lower than those of control VSMCs. The addition of angiotensin II to control VSMCs caused an increase in cell proliferation and protein synthesis. This increase was not observed in cirrhotic cells. There were more angiotensin II receptors in cirrhotic than in control VSMCs, but no significant changes in affinities were found. Angiotensin II-stimulated protein synthesis was dependent on protein kinase C activity and increased intracellular Ca2+ concentrations. CONCLUSIONS: This study shows abnormalities in growth characteristics and responsiveness to angiotensin II of cultured aortic VSMCs from rats with cirrhosis.

Portal vein thrombosis complicating hepatocellular carcinoma. Value of ultrasound-guided fine-needle biopsy of the thrombus in the therapeutic management.

During a 4-year period portal vein thrombosis was diagnosed in 20 Child class A patients with cirrhosis by means of ultrasound and ultrasound-Doppler study. Seventeen of them showed single or multiple focal liver lesions diagnosed as hepatocellular carcinoma by ultrasound-guided fine-needle biopsy and the remaining three a coarse liver echo-pattern without focal lesions. One patient was found to have developed portal vein thrombosis after the fifth ethanol injection of a single hepatocellular carcinoma lesion 17 mm in diameter. Ultrasound-guided fine-needle biopsy of the thrombus was performed on all the patients: portal vein thrombosis was neoplastic in 13 cases and non-neoplastic in seven cases (five patients with a single lesion; one with two lesions; one with coarse liver echo-pattern). Among the five patients with a single lesion, one had already been treated by percutaneous ethanol injection therapy. There were no complications related to the biopsy procedures. The diagnosis of non-neoplastic thrombosis allowed five new patients to be recruited for percutaneous ethanol injection treatment and allowed it to continue in the patient with portal vein thrombosis occurring after the fifth ethanol injection. The routine use of ultrasound-guided fine-needle biopsy of portal vein thrombosis yields an accurate diagnosis of the nature of the thrombus and can improve the selection for percutaneous ethanol injection treatment of patients with cirrhosis with hepatocellular carcinoma lesions.

Ultrasonographic signs of sliding gastric hiatal hernia and their prospective evaluation.

This study was conducted to identify the sonographic findings that might be used to diagnose sliding gastric hiatal hernia. We first performed a retrospective evaluation of 12 patients known to have sliding hiatal hernia and 18 normal controls. In the controls the esophagogastric junction could be visualized clearly in all cases and the alimentary tract section at the diaphragmatic hiatus ranged from 7.1 to 10.0 mm. The esophagogastric junction was not visualized in any of the hernia patients, whose alimentary tract diameters ranged from 16.0 to 21.0 mm. These two markers (nonvisualization of the junction and diameter greater than 16 mm) were then evaluated for their ability to predict the occurrence of sliding hiatus hernia in a prospective study of 38 patients subsequently diagnosed by means of barium contrast examinations and endoscopy. In this group, each sign had a positive predictive value of 100%. The negative predictive value of the alimentary tract diameter was 90%; that of nonvisualization of the esophagogastric junction was 94.7%. Inclusion of ultrasonography in the initial work-up of patients with symptoms of gastroesophageal reflux may reduce the need for more invasive diagnostic procedures.

Ultrasonographic signs of sliding, gastric, and hiatal hernia: their prospective evaluation.

This study was conducted to identify the sonographic findings that might be used to diagnose sliding gastric hiatal hernia. We first performed a retrospective evaluation of 12 patients known to have sliding hiatal hernia and 18 normal controls. In the controls the esophagogastric junction could be visualized clearly in all cases and the alimentary tract cross section at the diaphragmatic hiatus ranged from 7.1 to 10.0 mm. The esophagogastric junction was not visualized in any of the hernia patients, whose alimentary tract diameters measurements ranged from 16.0 to 21.0 mm. These two markers (non visualization of the function and diameter greater than 16 mm) were then evaluated for their ability to predict the occurrence of sliding hiatas hernia in a prospective study of 38 patients subsequently diagnosed by means of barium studies and endoscopy. In this group, each sign had a positive predictive value of 100%. The negative predictive value of the alimentary tract diameter was 90%; that of non-visualization of the esophagogastric junction was 94.7%. Inclusion of ultrasonography in the initial work-up of patients with symptoms of gastroesophageal reflux may reduce the need for more invasive diagnostic procedures.

Ultrasound-guided fine-needle biopsy of hepatocellular carcinoma: comparison between smear cytology and microhistology.

OBJECTIVES: The aims of this study were to evaluate the typing accuracy of smear cytology and microhistology and of their association in the diagnosis of hepatocellular carcinoma arising in liver cirrhosis, and to analyze the usefulness of smear cytology in the diagnosis of well-differentiated neoplasms. METHODS: One hundred sixty patients with hepatocellular carcinoma underwent an ultrasound-guided fine-needle biopsy, providing material for cytological and histological study. In 73 patients, a double biopsy with noncutting and cutting needles was performed (double-needle group), whereas in the remaining 87, a single biopsy with cutting needle was carried out (single-needle group). RESULTS: In the whole population examined, smear cytology, microhistology, and their association, provided the diagnosis of hepatocellular carcinoma in 128 (80%), 98 (61%), and 144 (90%) cases, respectively. The double-needle and the single-needle groups did not differ significantly as to typing accuracy. Smear cytology correctly diagnosed 54 of 64 neoplasms classified histologically as well-differentiated. CONCLUSIONS: Our results show that both smear cytology and microhistology should be applied immediately, when diagnosing hepatocellular carcinoma arising in liver cirrhosis, and that smear cytology is effective in the diagnosis of well-differentiated neoplasms.

Neoplastic seeding complicating percutaneous ethanol injection for treatment of hepatocellular carcinoma.

The authors describe a case of subcutaneous neoplastic seeding in the abdominal wall in a 67-year-old man with posthepatitic liver cirrhosis complicated by a single nodule of well-differentiated hepatocellular carcinoma. He was treated with percutaneous ethanol injection (PEI) performed under ultrasound guidance. The neoplastic seeding developed along the needle track used to carry out fine-needle biopsy and PEI and was diagnosed 6 months after the beginning of treatment.