Francisca Rivera

Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites

To identify prognostic factors in cirrhotic patients admitted to the hospital for the treatment of an episode of ascites, a survival analysis was performed in a series of 139 patients hospitalized in our Unit between 1980 and 1985. Mean follow-up was 12.8 +/- 14.2 mo (mean +/- SD). A total of 38 variables based on history, physical examination, hepatic biochemical tests, renal function tests, and endogenous vasoactive systems were analyzed for prognostic value. Eighteen of these variables had prognostic value in the univariate analysis. A multivariate analysis (Coxs regression method) disclosed that 7 of these 18 variables had independent prognostic value. Of these independent predictors of survival, mean arterial pressure and plasma norepinephrine concentration were the variables that best predicted prognosis. Two other variables that independently correlated with survival were urinary sodium excretion and glomerular filtration rate. The remaining three independent predictors of survival were nutritional status, hepatomegaly, and serum albumin concentration. Therefore, these findings indicate that, in patients with cirrhosis and ascites, parameters estimating systemic hemodynamics and renal function are better predictors of survival than those routinely used to estimate hepatic function.

Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E2 in cirrhosis. Relationship to functional renal failure and sodium and water excretion

Abstract. To investigate if functional renal failure in cirrhosis could be related to disturbances of vasoactive systems, plasma renin activity, plasma catecholamines and urinary prostaglandin E2 (PGE2) were determined in twenty‐two normal subjects and sixty‐five cirrhotics. Furthermore, in thirty‐three of these subjects, the effect of lysine‐acetylsalicylate (450 mg i.v.) on renal function was studied.

Circulating levels of endothelin in cirrhosis

BACKGROUND Current information concerning endothelin in cirrhosis is conflicting. Plasma endothelin concentration has been found to be increased in some studies and normal or reduced in others. The present study was aimed to investigate the plasma levels of endothelin in cirrhosis and to assess whether it is involved in the renal and hemodynamic disturbances and neurohumoral changes present in this condition. METHODS Renal function, plasma renin activity, and plasma concentration of aldosterone, norepinephrine, antidiuretic hormone, atrial natriuretic factor, and endothelin were measured in 9 healthy subjects, 7 compensated cirrhotics, and 25 cirrhotics with ascites (10 with functional renal failure). RESULTS Cirrhotics with ascites with and without functional renal failure showed higher endothelin levels (15.6 +/- 6.4 and 15.7 +/- 4.6 pg/mL, respectively; mean +/- SD) than compensated cirrhotics (6.4 +/- 1.8 pg/mL) and healthy subjects (3.4 +/- 1.0 pg/mL) (analysis of variance, F = 21.84; P < 0.001). These patients also showed higher plasma levels of renin, aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic factor, although plasma endothelin levels only correlated significantly with plasma atrial natriuretic factor (r = 0.73, P < 0.001) and antidiuretic hormone concentrations (r = 0.59, P < 0.001). In 7 additional nonazotemic cirrhotics with ascites, plasma renin activity and the plasma concentration of aldosterone and endothelin were measured before and 24 hours after the intravenous administration of a saline solution of human serum albumin. Volume expansion markedly suppressed renin and aldosterone but not endothelin (21.03 +/- 7.34 vs. 23.97 +/- 14.29 pg/mL). CONCLUSIONS Circulating plasma levels of endothelin are elevated in cirrhosis with ascites and do not decrease following plasma volume expansion.

Hepatic Nuclear Factor 1-α Directs Nucleosomal Hyperacetylation to Its Tissue-Specific Transcriptional Targets

ABSTRACT Mutations in the gene encoding hepatic nuclear factor 1-α (HNF1-α) cause a subtype of human diabetes resulting from selective pancreatic β-cell dysfunction. We have analyzed mice lacking HNF1-α to study how this protein controls β-cell-specific transcription in vivo. We show that HNF1-α is essential for the expression ofglut2 glucose transporter and L-type pyruvate kinase (pklr) genes in pancreatic insulin-producing cells, whereas in liver, kidney, or duodenum tissue, glut2 andpklr expression is maintained in the absence of HNF1-α. HNF1-α nevertheless occupies the endogenous glut2 andpklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones inglut2 and pklr promoter nucleosomes in pancreatic islets but not in liver cells, where glut2 andpklr chromatin remains hyperacetylated in the absence of HNF1-α. In contrast, the phenylalanine hydroxylase promoter requires HNF1-α for transcriptional activity and localized histone hyperacetylation only in liver tissue. Thus, different HNF1-α target genes have distinct requirements for HNF1-α in either pancreatic β-cells or liver cells. The results indicate that HNF1-α occupies target gene promoters in diverse tissues but plays an obligate role in transcriptional activation only in cellular- and promoter-specific contexts in which it is required to recruit histone acetylase activity. These findings provide genetic evidence based on a live mammalian system to establish that a single activator can be essential to direct nucleosomal hyperacetylation to transcriptional targets.

Plasma Renin Activity and Urinary Sodium Excretion as Prognostic Indicators in Nonazotemic Cirrhosis with Ascites

Azotemia is an ominous prognostic sign in cirrhosis with ascites. To investigate whether other renal disturbances are also prognostically significant, we studied the renin-aldosterone system and sodium excretion (UNaV) in 75 patients who had nonazotemic cirrhosis with ascites and related these to survival. On the basis of plasma renin activity patients were classified in two groups. Group I included 34 patients with normal renin activity (1.13 +/- 0.69 ng/mL . h) and Group II, 41 patients with high renin activity (7.46 +/- 3.86 ng/mL . h). The two groups differed significantly (p less than 0.001) in plasma aldosterone, UNaV, and wedged hepatic venous pressure but not in clinical features, liver function, glomerular filtration, and renal plasma flow. Patients of Group I lived significantly longer than those of Group II (the 50% survival rates were 28 months and 6 months, respectively). Survival curves obtained after grouping the patients according to UNaV (higher and lower than 10 meq/d) were almost identical to those obtained according to renin activity. The study results indicate that plasma renin activity and UNaV are of prognostic value in nonazotemic cirrhosis with ascites.

Renin, aldosterone and renal haemodynamics in cirrhosis with ascites.

Abstract. The interrelationships between the reninangiotensin‐aldosterone system, renal haemodynamics and urinary sodium excretion were investigated in fifty‐six non‐azotaemic cirrhotics with ascites. In twelve additional patients the renal renin secretion rate was also studied. Plasma renin activity and concentration and plasma aldosterone ranged from normal to very high values. There was a significant inverse relationship between plasma aldosterone and the urinary sodium excretion. Plasma aldosterone showed a highly significant direct correlation with plasma renin activity, and plasma renin concentration was closely and directly related to the estimated renin secretion rate. Neither plasma renin activity, plasma renin concentration nor the estimated renin secretion rate correlated with the renal plasma flow or the glomerular filtration rate. These results suggest that in non‐azotaemic cirrhosis with ascites the renin‐angiotensin‐aldosterone system is an important factor influencing sodium excretion, increased plasma renin and aldosterone concentrations are mainly due to an increased secretion rate, and total renal perfusion is not a major factor influencing renin secretion.

Genetic evidence that HNF-1α–dependent transcriptional control of HNF-4α is essential for human pancreatic β cell function

Mutations in the genes encoding hepatocyte nuclear factor 4α (HNF-4α) and HNF-1α impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4α is known to be an essential positive regulator of HNF-1α. More recent data demonstrates that HNF-4α expression is dependent on HNF-1α in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1α to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4α promoter (P1). Here we report that the expression of HNF-4α in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G → A mutation in a conserved nucleotide position of the HNF-1α binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1α, and consequently in reduced HNF-1α–dependent activation. These findings provide genetic evidence that HNF-1α serves as an upstream regulator of HNF-4α and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.

Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems.

BACKGROUND & AIMS Arterial vasodilation in cirrhosis may be related to increased circulating levels of vasodilators. This study was designed to assess the circulating levels of adrenomedullin, a recently described vasodilator peptide, in cirrhosis. METHODS Plasma adrenomedullin levels were measured in 17 healthy subjects and 34 cirrhotic patients. Hemodynamic parameters, renal function, and levels of vasoactive substances were also assessed. RESULTS Patients with ascites had increased adrenomedullin levels (289 +/- 47 pg/mL) compared with healthy subjects and patients without ascites (135 +/- 17 and 142 +/- 32 pg/mL, respectively; P < 0.05). Adrenomedullin levels correlated inversely with arterial pressure, glomerular filtration rate, and renal plasma flow and correlated directly with pulse rate, endothelin levels, and aldosterone and plasma renin activity. In cirrhotic patients, no significant differences in adrenomedullin levels were found between samples obtained from hepatic vein, renal vein, pulmonary artery, and femoral artery. Plasma expansion with albumin suppressed the renin-angiotensin system but did not affect adrenomedullin levels. CONCLUSIONS Circulating levels of adrenomedullin are increased in patients with ascites and correlate with hemodynamic and renal abnormalities and activation of vasoconstrictor systems. These increased levels seem to result from a generalized increase in adrenomedullin production from vascular tissue and are not suppressed by plasma expansion. Adrenomedullin may participate in the pathogenesis of arterial vasodilation in cirrhosis.

Gene Expression of Endothelin-1 and ETA and ETB Receptors in Human Cirrhosis: Relationship with Hepatic Hemodynamics

Previous experimental studies have suggested that the paracrine endothelin system may participate in the regulation of hepatic hemodynamics in cirrhosis. The present study assesses the relationship between increased portal pressure and preproET-1, ETA receptor and ETB receptor gene expression in human cirrhosis. PreproET-1, ETA receptor and ETB receptor mRNA abundance was estimated by quantitative PCR in human hepatic tissue from subjects with normal liver and in cirrhotic patients in whom a hepatic hemodynamic study was performed. The expression of the three transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from subjects without any histological alteration. Moreover, while no significant correlation was found between preproET-1 mRNA abundance and portal pressure, there was a highly significant direct relationship between ETA and ETB receptor gene expression and portal pressure in cirrhotic patients. These results indicate that the liver paracrine endothelin system is overactivated in human cirrhosis and that a direct relationship exists between endothelin receptor mRNA abundance and the degree of portal hypertension in these patients.

Mspl identifies a biallelic polymorphism in the promoter region of the α2A‐adrenergic receptor gene

Candidate gene: An increased activity of the sympathetic nervous system has been suggested to play a role in the pathophysiology of essential hypertension ( EHT). However, plasma catecholamine levels are not increased in these patients. An increased density of a,,-adrenergic receptors (a,,-AR) has been reported in patients with EHT (Mores et al. 1990, Calls et al. 1995). The activation of these receptors by epinephrine or norepinephrine promotes peripheral vasoconstriction and salt and water retention. The human cc,,-AR gene is located at 10q23-q25. The complete nucleotide sequence of this gene (HUMADRA2R) has been previously published (Fraser et al. 1989), and two restriction fragment length polymorphisms (DraI and Bsu36I RFLPs) have been reported to date (Hoehe et al. 1988, Sun et al. 1992). A significant association between DraI RFLP and essential hypertension has been described (Lockette et al. 1995, Svetkey et al. 1996), although there is no general agreement on these findings.