G. Buzzelli

Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial.

BACKGROUND/AIMS Diuretic treatment of ascites could result in intravascular volume depletion, electrolyte imbalance and renal impairment. We investigated whether intravascular volume expansion with albumin exert beneficial effects in cirrhosis with ascites. METHODS In protocol 1, 126 cirrhotic inpatients in whom ascites was not relieved following bed rest and a low-sodium diet, were randomly assigned to receive diuretics (group A) or diuretics plus albumin, 12.5 g/day (group B). In protocol 2, group A patients continued to receive diuretics and group B diuretics plus albumin (25 g/week) as outpatients and were followed up for 3 years. End points were: disappearance of ascites, duration of hospital stay (protocol 1), recurrence of ascites, hospital readmission and survival (protocol 2). RESULTS The cumulative rate of response to diuretic treatment of ascites was higher (p < 0.05) and hospital stay was shorter (20 +/- 1 versus 24 +/- 2 days, p < 0.05) in group B than in group A patients. After discharge, group B patients had a lower cumulative probability of developing ascites (19%, 56%, 69% versus 30%, 79% and 82% at 12, 24 and 36 months, p < 0.02) and a lower probability of readmission to the hospital (15%, 56%, 69% versus 27%, 74% and 79%, respectively, p < 0.02). Survival was similar in the two groups. CONCLUSIONS Albumin is effective in improving the rate of response and preventing recurrence of ascites in cirrhotic patients with ascites receiving diuretics. However, the cost/benefit ratio was favorable to albumin in protocol 1 but not in protocol 2.

Relevance of inapparent coinfection by hepatitis B virus in alpha interferon-treated patients with hepatitis C virus chronic hepatitis.

The aim of the study was to investigate whether an “inapparent” coinfection by hepatitis B virus (HBV) in anti‐HCV‐positive chronic liver disease patients may influence interferon (IFN) response. Fourteen anti‐HCV‐positive, hepatitis B surface antigen (HBsAg)‐negative but serum HBV‐DNA‐positive patients and 111 anti‐HCV‐positive, HBsAg‐negative, and HBV‐DNA‐negative patients with chronic hepatitis were treated with 3 MU of recombinant α‐2a IFN 3/week for 1.2 months. Serum HBV‐DNA and HCV‐RNA were determined before treatment, after 6–12 months, and at the time of alanine aminotransferase (ALT) flare‐up by HBV polymerase chain reaction (PCR) and HCV PCR, respectively. IgM anti‐HBc were tested using the IMx Core‐M assay (Abbott Laboratories, North Chigago, IL). By the end of treatment, ALT values had become normal in 4/14 HBV‐DNA‐positive patients (28%), but all “responders” (4/4) relapsed. IgM anti‐HBc was detected both before treatment and during ALT elevation in three patients and only during ALT relapse in another three. In the remaining 111 patients, a biochemical response to IFN treatment was observed in 54% and relapse of ALT values in 47%. “Inapparent” HBV/HCV coinfection may be implicated in cases of resistance to IFN. HBV replication and HBV‐related liver damage may persist in patients in whom HCV replication was inhibited by current doses of IFN, as suggested also by the presence of IgM anti‐HBc in some cases. Further studies will show the effect of different treatment schedules. HBV‐DNA and/or IgM anti‐HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding of intervirus relationships and mechanisms involved in multiple hepatitis virus infections. J. Med. Virol. 51:313–318, 1997.

Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver

BACKGROUND In cirrhotic patients with ascites, captopril has deleterious effects on renal function, which have been referred to as captopril-induced arterial hypotension. The effects of this drug on renal function in cirrhosis were evaluated using low-dose captopril, thereby avoiding any change in arterial pressure. METHODS In a randomized, double-blind, placebo controlled, cross-over trial, the effects of 12.5 mg captopril on renal plasma flow, glomerular filtration rate (measured by radioisotopic techniques), and sodium excretion in healthy controls and cirrhotic patients with and without ascites were determined. RESULTS In healthy subjects, captopril only induced a significant, 18% increase in renal plasma flow. In contrast, glomerular filtration rate significantly decreased in patients with (from 108 +/- 7 to 78 +/- 9 mL/min) and without ascites (from 102 +/- 4 to 88 +/- 3 mL/min), whereas renal plasma flow did not change. Urinary sodium excretion also significantly decreased in ascitic patients (from 43.8 +/- 4.4 to 30.6 +/- 3.8 mumol/min). CONCLUSIONS These data suggest that angiotensin II contributes to maintain renal hemodynamics in cirrhosis with and without ascites.

THERAPEUTIC AND ANTILIPOPEROXIDANT EFFECTS OF SILYBIN-PHOSPHATIDYLCHOLINE COMPLEX IN CHRONIC LIVER DISEASE: PRELIMINARY RESULTS

Abstract Eight patients (two men and six women; mean age, 54.6 + 5 years) with viral chronic active hepatitis were treated with silipide (IdB1016), a new silybin-phosphatidylcholine complex, for 2 months. After treatment with IdB1016, serum malondialdehyde levels decreased by 36%, and the quantitative liver function evaluation, as expressed by galactose elimination capacity, increased by 15%. A statistically significant reduction ( P

Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection

SummaryThe possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an “inapparent” coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an “inapparent” coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant α-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6–12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5′NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all “responders” (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. “Inapparent” HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.

Functional Renal Alterations in Chronic Liver Diseases

83 patients with chronic active hepatitis (CAH), 38 of them with cirrhosis, were studied and compared with 10 control subjects suffering from chronic persistent hepatitis (CPH). Tubular acidosis frequently was found in our cases. Renal plasma flow and glomerular filtration rate were significantly decreased in CAH when compared with CPH. Selective renal arteriography showed evident decrease of arterial flow in the outer cortex. Selective renal scan with 99mTc microspheres of human albumin showed a frequent escape of the tracer from the kidney to the lung. PGE1 and PGE2 levels appeared higher in the renal artery than in the vein and were significantly more elevated in 9 cases with cirrhosis vs. 13 controls. These results suggest the frequent functional impairment of the kidney also in the early stages of CAH, with an increase of PGE levels and an opening of intrarenal shunts.

Systemic Hemodynamics and Renal Function in Cirrhotic Patients during Plasma Volume Expansion

Systemic hemodynamic impairment (hepatocirculatory failure) has been suggested as one of the possible factors which may explain the renal hemodynamic alterations found in the late stage of liver cirrhosis, typical of the hepatorenal syndrome. 20 patients, divided into two groups of 10 sodium retainers and 10 sodium excretors, affected by liver cirrhosis with portal hypertension and ascites, were studied. Renal functional parameters (diuresis, urinary and plasma electrolytes, urine to plasma osmolality and creatinine ratios and creatinine clearance) were evaluated before and after acute volume expansion with 1,000 ml of 10% dextran in saline, infused through a catheter located in the right atrium. Hemodynamic tests (cardiac index, systemic vascular resistance, right atrial pressure and capillary wedge pressure) were performed before, during and after expansion. Cardiac index decreased in 6 patients (sodium excretors) after a 500-ml infusion and rose again after 1,000 ml in 5 of them. The remaining 14 patients showed a progressive and significant increase of cardiac index. A strong inverse relationship between cardiac index and systemic vascular resistance was observed (r = -0.87; p less than 0.001). The mean left-ventricular function curve showed a slow response in most sodium excretors and a normal response in the sodium-retaining group, without significant difference between the two groups. Sodium excretion significantly improved after expansion in both groups of patients. No relationship was found between hemodynamic response and renal function. These data show that cardiocirculatory function is normal, even in sodium-retaining cirrhotics.

Possible roles of insulin, glucagon, growth hormone and free fatty acids in the pathogenesis of insulin resistance of subjects with chronic liver diseases

SummaryIn the present investigation, insulin sensitivity and fasting levels of insulin, C-peptide, glucagon, growth hormone and free fatty acids were estimated and correlated in a population of individuals suffering from liver cirrhosis or chronic hepatitis. Insulin sensitivity, assessed by glucose disappearance rate after intravenous bolus injection of insulin, was reduced but not significantly different from controls in subjects with chronic persistent hepatitis, while it was significantly reduced in individuals suffering from chronic active hepatitis or liver cirrhosis. Insulin, glucagon, growth hormone, and free fatty acid fasting levels were higher than in healthy subjects in individuals with liver cirrhosis or chronic active hepatitis but not in subjects with chronic persistent hepatitis. C-peptide concentrations did not differ from controls in subjects with liver disease. Significant negative correlations occurred between coefficients of insulin sensitivity and fasting concentrations of insulin, glucagon, growth hormone and free fatty acids, but not with fasting levels of C-peptide. Positive relationships were present between fasting levels of free fatty acids and both glucagon and growth hormone concentrations. These results show that, unlike subjects with liver cirrhosis and chronic active hepatitis, individuals suffering from chronic persistent hepatitis do not differ from healthy subjects in insulin sensitivity and fasting levels of insulin, glucagon, growth hormone, and free fatty acids. Moreover, they suggest that both hyperinsulinemia and high concentrations of counterregulatory substances might play a role in the pathogenesis of insulin resistance in subjects suffering from chronic liver disease.

Cardiac autonomic modulation and incidence of late potentials in essential hypertension : role of age, sex, ventricular mass and remodeling

The influence of age, sex, left ventricular hypertrophy (LVH) and geometry on the autonomic activity to the heart was investigated in 96 hypertensive out-patients (53 men, mean age 53 ± 9 years) and 39 healthy subjects (19 men, mean age 43 ± 1 years). Using 24-h Holter recordings, time [the standard deviation of all RR intervals (SDNN) and the square root of the mean of the squared differences between adjacent normal RR intervals (RMSSD)] and power spectral analysis of RR intervals [Fast Fourier algorithm, low/high frequency (LF/HF) ratio] were calculated over 24 h, daytime (D) and night-time (N) periods in all subjects. Signal averaged electro-cardiogram was recorded in 50 patients to detect late potentials. Stepwise multiple linear regression analysis showed that the 24-h LF/HF ratio was influenced by age and sex, D-LF/HF by age and N-LF/HF by sex, a higher LF/HF ratio being found in younger patients and in men. These data suggest a more prominent sympathetic modulation of cardiac activity in these groups. No differences in RR period variations were observed between patients with or without LVH. Late potentials were observed in 10 patients, and did not correlate with any of the measured parameters.

Vasoactive factors in the mechanism of renal sodium handling in cirrhotics: The effect of acute plasma expansion

Twenty cirrhotic patients with ascites, divided into two groups of 10 each, according to their daily urinary sodium excretion (sodium retainers and sodium excretors) and given a diet of 75 mEq of sodium daily, underwent acute plasma volume expansion with 1,000 ml of 10% dextran in saline, infused through a catheter located in the right atrium. Even if a significant increase in sodium excretion was observed in both groups (p less than 0.001 in sodium excretors and p less than 0.05 in sodium retainers), plasma expansion did not reverse sodium retention in sodium retainers. A significant increase in creatinine clearance was found only in sodium retainers (p less than 0.02). Basal plasma renin activity and plasma aldosterone were elevated only in a few patients of both groups. The renin-angiotensin-aldosterone system was highly responsive to plasma expansion. Sodium retainers, who showed an ineffective natriuretic response after expansion, were able to suppress both plasma renin activity and plasma aldosterone in an analogous manner to the sodium-excreting group. This result lends strong support to the concept that the elevated aldosterone level in cirrhosis is not the major determinant of sodium retention. The kallikrein-kinin system was responsive to volume stimulus, since a decrease in kallikrein excretion was noted. It was significant in sodium retainers (p less than 0.05). Plasma PGE1,2 levels were significantly higher in sodium retainers than in controls. This may suggest that there is an activation of the intrarenal prostaglandin system, which could play a protective role against renal ischaemia. After volume expansion, PGE1,2 increased, but not significantly. Octopamine appeared unrelated to sodium excretion and unresponsive to volume stimulus. Endotoxins did not seem to be involved in renal sodium handling. Plasma volume expansion seemed effective in inducing a reduction of vasoconstrictor and sodium-retaining factors, such as the renin-angiotensin-aldosterone system. It is possible to suggest that volume expansion could increase PGE1,2. Plasma volume expansion produced different rates of sodium excretion in the two groups of patients and this suggests that impaired sodium handling in cirrhosis could, to some extent, be independent of effective plasma volume.