Serum endothelin and atrial natriuretic peptide in cirrhotic patients with ascites and hepatorenal syndrome

BACKGROUND: The pathogenesis of cirrhotic ascites and hepatorenal syndrome remains unresolved. The involvement of both endothelin-1 and atrial natriuretic peptide have recently been suggested. This study investigated the concentrations of serum endothelin and atrial natriuretic peptide in cirrhotic patients. METHODS: Seven healthy subjects and 31 cirrhotic patients were studied. Cirrhotic patients were divided into three groups: Group I, 16 cirrhotic patients without ascites; Group II, 10 cirrhotic patients with ascites, but without hepatorenal syndrome; and Group III, five cirrhotic patients with hepatorenal syndrome and ascites. Their sera were analyzed for endothelin-1 and atrial natriuretic peptide concentrations. RESULTS: Cirrhotic patients with ascites, Group II and Group III, had higher plasma endothelin-1 concentrations (15.9 +/- 2.3 pg/ml and 24 +/- 2.1 pg/ml, respectively) than normal subjects and compensated cirrhotics (3.8 +/- 0.7 pg/ml and 6.4 +/- 1.1 pg/ml, respectively); p < 0.001). Atrial natriuretic peptide concentrations were also significantly higher in cirrhotic patients than in normal subjects (p < 0.025). Plasma endothelin-1 concentration had a negative correlation with creatinine clearance (r = -0.65, p < 0.001), as did atrial natriuretic peptide concentrations (r = -0.44, p = 0.012). Plasma endothelin-1 correlated significantly with atrial natriuretic peptide concentrations (r = 0.38, p = 0.035). CONCLUSIONS: Both endothelin-1 and atrial natriuretic peptide concentrations were elevated in cirrhotic patients with ascites and hepatorenal syndrome. Endothelin-1 may have a negative impact on renal function. Our data also suggested that impaired responsiveness rather than impaired secretion of atrial natriuretic peptide is responsible for sodium retention in cirrhotic patients with ascites.     

Genotyping of the CYP1A1 and GSTM1 genes in esophageal carcinoma patients with special reference to smoking

OBJECTIVES: Patients with cirrhosis and ascites have high plasma levels of atrial natriuretic peptide (ANP). Pharmacological doses of this hormone usually worsen systemic hemodynamics of cirrhotic patients. We assessed whether ANP influences cardiovascular homeostasis and renal function in patients with compensated cirrhosis at plasma levels comparable to those observed in patients with cirrhosis and ascites. METHODS: Radionuclide angiocardiography was performed in eight compensated cirrhotic patients during placebo (three periods of 15 min each) and ANP infusion (2, 4, and 6 pmol/kg.min for 15 min each), together with appropriate blood and urine sampling, to evaluate left ventricular diastolic, systolic, and stroke volume, heart rate, cardiac output, arterial pressure, peripheral vascular resistance, creatinine clearance, urinary sodium excretion, plasma renin activity, plasma aldosterone, norepinephrine and hematocrit. RESULTS: The infusion increased plasma ANP up to levels (52.03 +/- 2.29 pmol/L) comparable with those observed in 35 patients with ascites (46.42 +/- 1.57 pmol/ L). This increment was associated with significant reductions in left ventricular end diastolic volume, stroke volume, cardiac index (from 3.7 +/- 0.7 to 3.1 +/- 0.5 L/min.m2, p < 0.05) and mean arterial pressure (from 96.7 +/- 6.5 to 88.5 +/- 9.5 mmHg, p < 0.05), while heart rate and hematocrit significantly increased. Peripheral vascular resistance did not change. These hemodynamic effects occurred despite significant increases in plasma renin activity and norepinephrine. ANP also induced increases in creatinine clearance, urinary sodium excretion, and fractional sodium excretion. CONCLUSIONS: Low-dose ANP affected cardiovascular homeostasis and renal sodium handling in compensated cirrhosis, suggesting that this hormone may be involved in the pathophysiology of systemic hemodynamic and renal functional abnormalities of cirrhosis.     

Reimmunization after allogeneic bone marrow transplantation

BACKGROUND/AIMS: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia. METHODS: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection. RESULTS: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin. CONCLUSIONS: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.     

Vagal dysfunction and impaired urinary sodium and water excretion in cirrhosis

OBJECTIVE: To evaluate the possible role of vagal impairment in the disturbances of urinary sodium and water excretion observed in cirrhosis. METHODS: Standard cardiovascular reflex tests were used to assess Autonomic function in 11 cirrhotic patients, and the response to an acute intravenous water load was determined. Changes in plasma noradrenaline, antidiuretic hormone, renin, and atrial natriuretic peptide also were evaluated. RESULTS: Patients with vagal dysfunction were shown to have significantly impaired urinary sodium and water excretion, compared with those whose cardiovascular tests were normal (5-h urinary sodium excretion, 32.3 +/- 9.0 vs. 69.4 +/- 12.7 mmol, p < 0.05; % water load excreted at 5 h, 67.8 +/- 10.5 vs. 109.2 +/- 3.67%, p < 0.008). This was associated with higher circulating noradrenaline, renin, and antidiuretic hormone levels after the water load in the vagal dysfunction group. Urinary sodium excretion correlated with the heart rate variation on deep breathing (r = 0.74, p < 0.013) and the heart rate response to atropine (r = 0.75, p < 0.020); the % water load excreted correlated with the number of abnormal cardiovascular tests in each patient (rS = 0.67, p < 0.02). Although patients with vagal abnormalities had worse liver function, urinary sodium and water excretion correlated better with parasympathetic tests than with standard parameters of hepatic function. CONCLUSIONS: The presence of vagal impairment in cirrhosis appears to be associated with impaired urinary sodium and water excretion, as well as disturbances in circulating vasoactive hormones. These findings could be due to an afferent defect resulting in diminished inhibitory input from intrathoracic volume and arterial baroreceptors, although a confounding effect of worse hepatic function in patients with vagal impairment cannot be excluded.     

Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide

BACKGROUND: It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS: Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS: Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS: Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.     

Oxygen administration increases plasma digoxin-like substance and renal sodium excretion in chronic hypoxic patients

Despite the absence of cardiac or renal pathologies, edema and mild hyponatremia may often occur in patients affected by chronic obstructive pulmonary disease (COPD). Therefore, it has been suggested that hypoxia may influence the release of different hormones regulating renal sodium handling. To evaluate the effect of hyperoxia and O2 removal on plasma digitalis-like substance (DLS) levels, 9 patients affected by COPD and 7 normal subjects were studied. After 1 h in supine position, O2 was administered for 3 h by a tight-fitting face-mask. Blood samples for plasma DLS were taken at time 0, 60, 180 min and then for 3 h after O2 removal. In normal subjects, plasma DLS did not vary after O2 administration (from basal values of 162.25 +/- 8.59 to 107.75 +/- 6.65 pg/ml at 180 min; NS), and O2 removal (143.7 +/- 16.87 pg/ml after 3 h from O2 removal; NS). On the contrary, in patients affected by COPD, plasma DLS levels increased during O2 administration (from basal values of 138.98 +/- 8.31 to 202.14 +/- 8.21 pg/ml at 180 min; p < 0.05), and returned to baseline levels (142.59 +/- 8.28 pg/ml) 3 h after O2 removal. In the same patients, DLS increase was accompanied by a rise in Na+ excretion (from 0.08 +/- 0.01 at time 0 to 0.16 +/- 0.02 mEq/min after 3 h of O2 administration; p < 0.05). In conclusion, our findings showed an oxygen-related increase in plasma DLS levels and in urinary Na+ excretion in patients affected by COPD. This phenomenon could promote Na+ urinary loss during prolonged O2 therapy in these patients and should be taken into account in their management.     

Natriuretic effect of an adenosine-1 receptor antagonist in cirrhotic patients with ascites

BACKGROUND & AIMS: The sodium and water retention and renal vasoconstriction exhibited by patients with cirrhotic ascites are similar to the changes observed by stimulation of renal adenosine 1 receptors. The aim of this study was to investigate the effects of FK352 (an adenosine 1 antagonist) on renal and systemic hemodynamics and renal function in cirrhotic patients with ascites. METHODS: p-Aminohippuric acid and inulin clearance, urine flow rate, sodium and potassium excretion, and free water clearance were measured for 2 hours before and after FK352 administration. Cardiac output, systemic vascular resistance, plasma angiotensin II level, plasma renin activity, and noradrenaline, adrenaline, and adenosine 3', 5'-cyclic monophosphate (cAMP) levels were also measured before and after FK352. RESULTS: Urine sodium excretion and urine flow rate increased after FK352 by a mean of 199.9% +/- 43.0% (P < 0.001) and 51.2% +/- 17.5% (P < 0.02), respectively. Plasma cAMP and angiotensin II levels and plasma renin activity also increased by 10. 8% +/- 3.2% (P < 0.01), 36.9% +/- 11.3% (P < 0.01), and 247.9% +/- 82.6% (P < 0.02), respectively. No change was detected in any other parameter. CONCLUSIONS: The isokaliuretic improvement in natriuresis and diuresis suggests a role for adenosine 1 antagonism in the treatment of the renal abnormalities found in advanced cirrhosis.     

Effect of subcutaneous administration of octreotide on endogenous vasoactive systems and renal function in cirrhotic patients with ascites

Splanchnic and systemic arteriolar vasodilation plays an important role in ascites formation in cirrhosis. Octreotide produces splanchnic vasoconstriction, but the effects on systemic hemodynamics and renal function are controversial. This study evaluated the effect of subcutaneous octreotide administration on systemic hemodynamics, endogenous vasoactive systems, and renal function in cirrhotic patients with ascites. Twenty patients were included: 10 received octreotide 250 microg/12 hr subcutaneously (for five days), and 10 did not. No statistically significant changes were found in mean arterial pressure and cardiac rate. Octreotide induced a statistically significant decrease in plasma renin activity (P < 0.01), plasma aldosterone (P = 0.01) and plasma glucagon (P < 0.05). No significant variations were observed in other systemic vasoactive substances (nitric oxide and prostacyclin). Renal function was not modified in either group. In conclusion, in cirrhotic patients with ascites, subcutaneous octreotide administration decreases plasma glucagon, renin activity, and aldosterone without changing in systemic hemodynamics or renal function.     

Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites

OBJECTIVE: Large volume paracentesis is an effective treatment for refractory ascites, but the need for routine infusion of albumin or other volume expanders remains controversial. The aim of this study was to assess the short term effects of a single 5-L paracentesis without albumin replacement on total central blood volume, systemic and renal hemodynamics, sodium homeostasis, and neurohumoral factors. PATIENTS AND METHODS: Twelve patients with biopsy-proven cirrhosis and tense, diuretic-resistant ascites were studied before and 48 h after a single 5-L paracentesis without albumin infusion. Systemic hemodynamics and total central blood volume were assessed using radionuclide angiography. Glomerular filtration rate and effective renal plasma flow were measured by inulin and para-aminohippurate clearances, respectively. Lithium clearance was used as an index of proximal tubular reabsorption of sodium. In addition, plasma concentrations of neurohumoral factors were determined. RESULTS: Total central blood volume was 2.41 +/- 0.33 L/m2 (mean +/- SEM) before and 2.34 +/- 0.18 L/m2 48 h after large volume paracentesis (p = 0.76). Similarly, no differences were detected in the cardiac index, glomerular filtration rate, effective renal plasma flow, urinary sodium excretion, hematocrit, plasma renin activity, or concentrations of plasma aldosterone, norepinephrine, or atrial natriuretic factor. CONCLUSIONS: A single large volume paracentesis without albumin replacement causes no disturbances in systemic and renal hemodynamics 48 h after the procedure. These results suggest that a single 5-L paracentesis without albumin infusion is a safe and satisfactory short term option for the management of patients with cirrhosis and tense, diuretic-resistant ascites.     

Echo-Doppler evaluation of the renal arterial flow in hepatic cirrhosis

In liver cirrhosis the sodium retention depends on a decreased renal perfusion by arteriolar vasoconstriction. To evaluate the usefulness of echo-Doppler in detecting such hemodynamic impairment, we studied 16 cirrhotic patients and 16 healthy subjects as control group. We measured Pulsatility Index (P.I.) and Resistivity Index (R.I.). Both parameters resulted to be statistically higher in cirrhotic patients than in controls; moreover they resulted to be higher in cirrhotics with ascites than in those without. Therefore echo-Doppler can detect intraparenchymal renal vasoconstriction in cirrhosis, this impaired perfusion is already evident before ascites formation.     

Pioneer in public health education: Roscoe Conkling Brown

In order to study the influence of ageing on the hormonal function of the endothelium in man, plasma endothelin levels were measured in 11 normal young persons (mean aged 25.7 +/- 1.8 years) and in 16 apparently healthy elderly subjects (mean 87.5 +/- 5.4 years) without anamnestic or clinical signs of symptomatic atherosclerosis. The mean plasma level +/- SD of endothelin was 2.72 +/- 0.61 pg/ml in elderly subjects and 2.09 +/- 0.66 in young subjects. The difference was statistically significant (p < 0.05). Various humoral or local age-related environmental factors may be responsible for this result. In particular increased vascular production of endothelin may be the response to endothelial cell damage caused by an asymptomatic atherosclerotic process. Studies still need to define whether enhanced plasma endothelin levels in elderly subjects not suffering from symptomatic atherosclerosis are the consequence of ageing alone or an ongoing but clinically silent atherosclerotic process.     

Relation of endothelins to volume regulating neurohumoral systems in patients with cirrhosis of the liver

The aim of the present study was to investigate the relationship between ET plasma concentrations and other hormonal systems in acute volume regulation of patients with cirrhosis. Ten healthy controls and 10 cirrhotic patients, five without and five with ascites were studied after 1 h in a sitting posture and subsequently subjected to 1 h head-out water immersion. Blood was collected for determinations of ET-1, ET-3, ANF, aldosterone, renin activity and noradrenaline. In addition, in 10 patients with compensated cirrhosis the effect of loop diuretics on ET-3, aldosterone and renin was studied. ETs in cirrhosis were significantly (P < 0.01) higher than in controls both before (ET-1, 19.6 +/- 1.3 pgmL-1 vs. 11.8 +/- 0.4 pgmL-1; ET-3, 18.5 +/- 1.4 pgmL-1 vs. 9.5 +/- 0.5 pgmL-1) and after water immersion (ET-1, 18.6 +/- 1.2 pgmL-1 vs. 12.4 +/- 0.3 pgmL-1; ET-3, 18.7 +/- 1.7 pgmL-1 vs. 10.0 +/- 0.5 pgmL-1). In cirrhotic patients, basal and immersion concentrations of ET-1 were significantly correlated to noradrenaline plasma concentrations (r = 0.79, P < 0.05). ET-3 plasma concentrations in cirrhosis were correlated to renin activity (r = 0.65, P < 0.05). Furthermore, ET-3 in cirrhosis was inversely correlated to systolic and mean arterial blood pressure (r = -0.55, P < 0.01 and r = -0.50, P < 0.05; respectively). To investigate the effect of hypovolaemia in compensated cirrhosis, 10 patients without ascites were studied before and after treatment with loop diuretics. In compensated cirrhosis ET-3 was significantly increased 6h after oral diuretic treatment (17.9 +/- 1.0 pgmL-1 vs. 15.5 +/- 0.4 pgmL-1, P < 0.001). The presented data demonstrate relations of endothelins, particularly of ET-3 to neurohumoral systems in patients with cirrhosis of the liver.     

Clinical significance of plasma endothelin levels in patients with biliary atresia

Biliary atresia (BA) is the end-result of a destructive inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tracts with the development of biliary cirrhosis and portal hypertension (PH). Endothelins (ET) are 21-amino-acid peptides of endothelial origin with potent vasoconstrictor activity that bind to various cells of the liver. Nothing is presently known about plasma ET levels in BA. The aim of this study was to determine the clinical significance of plasma ET levels in patients with BA after hepatic portoenterostomy (Kasai's procedure) and to correlate these with liver function tests (LFT) and PH. We measured plasma concentrations of ET in 19 patients with BA (5 boys and 14 girls; mean age 11.6 +/- 5.5 years) after portoenterostomy and 10 age-matched controls. Patients were grouped according to outcome based on LFT: group A consisted of 9 patients with an "unfavorable outcome" and Group B 10 patients with a "favorable outcome". The plasma ET levels were measured using a highly sensitive and specific enzyme immunometeric assay (EIA). No patient had ascites or hepatorenal syndrome. Plasma ET levels were significantly higher in patients with BA than in controls (3.42 +/- 0.42 vs 1.75 +/- 0.39 pg/ml, respectively; P < 0.01) and in patients in group A than in group B. (3.75 +/- 0.25 vs 3.06 +/- 0.23 pg/ml, respectively; P < 0.01). In group A, plasma ET levels were higher in patients with PH (n = 4) than in those without PH (n = 5) (3.99 +/- 0.06 vs 3.64 +/- 0.22 pg/ml, respectively; P < 0.05). We conclude that plasma ET levels are high in patients with BA, especially those with severe biliary cirrhosis, and that ET may partially contribute to development of PH in BA. The results of the present study also suggest that plasma ET concentrations may be a useful marker in the follow-up of patients with BA.     

Hepatorenal reflex plays an important role in natriuresis after high-NaCl food intake in conscious dogs

Responses of renal nerve activity and urinary Na+ and Cl- excretion were examined in chronically instrumented conscious dogs through feedings of boiled rice with or without NaCl. The boiled rice (20 g/kg body wt) without NaCl did not influence plasma Na+ and Cl- concentrations, renal nerve activity, or urinary Na+ excretion but decreased urinary Cl- excretion. On the other hand, boiled rice containing NaCl (0.4 g/kg body wt) increased plasma Na+ (+3.8 +/- 0.7 meq/l) and Cl- (+3.0 +/- 1.5 meq/l) concentrations, then decreased renal nerve activity by 61 +/- 4%, and increased urinary Na+ and Cl- excretions. In dogs with hepatic denervation, a decrease in renal nerve activity, which was observed in intact dogs in response to the high-NaCl food intake, was completely abolished along with significant attenuation of postprandial natriuresis. That is, only 9 +/- 5% of the loaded Na+ and 7 +/- 3% of the loaded Cl- were excreted during 4 consecutive hours in hepatic-denervated dogs, whereas 36 +/- 5% of the loaded Na+ and 36 +/- 4% of the loaded Cl- were excreted in intact dogs. In dogs with renal denervation, postprandial natriuresis was also attenuated. These results indicate that the high-NaCl food intake elicits a decrease in renal nerve activity, the decrease is predominantly mediated by the hepatic nerves, and the decrease in renal nerve activity plays an important role in augmentation of urinary Na+ and Cl- excretion. Thus, the hepatorenal reflex may play an important role in controlling extracellular fluid homeostasis during food intake.     

Refractory ascites in cirrhosis: roles of volume expansion and plasma atrial natriuretic factor level elevation

Cirrhotic patients with ascites refractory to diuretics also have blunted response to marked elevations of plasma atrial natriuretic factor levels alone or to moderate intravascular volume expansion by head-out water immersion. However, these patients usually undergo natriuresis after peritoneovenous shunting. To dissect the factors responsible for this response, we studied the effects on separate days of moderate intravascular volume expansion and highly elevated plasma atrial natriuretic factor levels (head-out water immersion and atrial natriuretic factor infusion) or marked volume expansion and moderate plasma atrial natriuretic factor level elevation (head-out water immersion and albumin infusion) in 13 alcoholic cirrhotic patients with massive ascites. Three of these patients, who responded to initial head-out water immersion with a negative sodium balance, served as controls. Unresponsiveness to head-out water immersion was confirmed in the remaining 10 patients on both days on the basis of blunted natriuretic response (urinary sodium excretion < 0.8 mmol/hr after 2 hr). In contrast, these 10 refractory patients were able to achieve negative sodium balance with both combinations. Mean urinary sodium excretion increased from a baseline level of 0.13 +/- 0.10 mmol/hr to a peak level of 2.29 +/- 0.61 mmol/hr after head-out water immersion and atrial natriuretic factor infusion and from 0.10 +/- 0.3 mmol/hr to 1.61 +/- 0.62 mmol/hr after head-out water immersion and albumin infusion. Both maneuvers were associated with suppression of plasma renin activity and serum aldosterone levels. With head-out water immersion and atrial natriuretic factor infusion, we noted a significant increase in 5' cyclic GMP levels, a second messenger of atrial natriuretic factor, indicating possible activation of atrial natriuretic factor receptors at the inner medullary collecting ducts. In contrast, with head-out water immersion and albumin infusion no such increase in levels occurred, indicating that the increase in urinary sodium excretion was mainly due to increased delivery of sodium to the cortical distal nephron, as indicated by a disproportionate increase in urinary potassium excretion. In conclusion, massive (as opposed to moderate) volume expansion or greatly elevated levels of plasma atrial natriuretic factor associated with moderate volume expansion can improve blunted atrial natriuretic factor responsiveness in cirrhotic patients with refractory ascites. This appears to be achieved by way of a marked increase in distal delivery of filtrate in the kidney, with or without activation of distal atrial natriuretic factor receptors in the inner medullary collecting ducts.     

Predicting hospital mortality in cirrhotic patients: comparison of Child-Pugh and Acute Physiology, Age and Chronic Health Evaluation (APACHE III) scoring systems

OBJECTIVE: The severity of hepatic abnormalities and extent of dysfunction of other organ systems influences prognosis for cirrhosis. The Child-Pugh system has been used to classify cirrhotic patients into good, intermediate, or poor risk categories in evaluation and therapy. Disregard for cardiorespiratory, renal, electrolyte balance, and acid base status limits its predictive accuracy. We evaluated the accuracy of Acute Physiology and Chronic Health Evaluation (APACHE III) to predict short term hospital mortality in patients with liver cirrhosis. METHODS: A total of 282 patients were prospectively enrolled. Child-Pugh and APACHE III scores were recorded on day 1 for each patient. RESULTS: Mean age was 51.7+/-11.3 yr, with 65% men and 35% women; 57% presented with upper GI bleeding, 47% encephalopathy, 9% hepatorenal syndrome, and 7% hepatocellular carcinoma. Sixty-three patients (22%) died. Major causes of death were upper GI bleeding 38%, liver failure 21%, hepatorenal syndrome 19%, hepatocellular carcinoma 4%, and spontaneous bacterial peritonitis 6%. Child-Pugh and APACHE III scores for survivors (8.6+/-2.3 and 58.9+/-35.1) were lower than those for nonsurvivors (10.9+/-2.7 and 87.4+/-30.3) (p < 0.001). Using discriminant analysis, APACHE III correctly identified 75% of cases vs 67% of cases for Child-Pugh (p < 0.05). When information regarding ascites and prothrombin time was added to APACHE III, 81% of cases were correctly classified. CONCLUSION: The APACHE III scoring system is superior to Child-Pugh for prognosticating short term survival of cirrhotic patients. Prognostic accuracy of APACHE III can be enhanced by incorporating information regarding ascites and prothrombin time prolongation.     

Nocturnal blood pressure and relation to vasoactive hormones and renal function in hypertension and chronic renal failure

The purpose of this study was to assess the blood pressure profile and to measure vasoactive hormones in patients with essential hypertension (n=61), secondary hypertension (n=32) and chronic renal failure (n=32) matched with healthy control subjects (n=35), and to study the relationship between circadian changes in blood pressure and baseline levels of vasoactive hormones and renal function. Non-invasive, automatic blood pressure measurement was performed for 24 or 48 h. Venous plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin, atrial natriuretic peptide and endothelin were measured. The mean 24-h blood pressure was higher in all groups of hypertensive patients than in control subjects. The nocturnal blood pressure fall was preserved in essential hypertension, in contrast to secondary hypertension in which it was attenuated. In the patients with chronic renal failure the 24-h mean blood pressure was the same as in the controls. Night-time blood pressure was higher among the chronic renal failure patients than in the control group, and the nightly blood pressure fall in both diastolic and systolic blood pressure was reduced. Plasma concentrations of renin activity, arginine vasopressin, atrial natriuretic peptide, aldosterone and endothelin were significantly increased in secondary hypertension and chronic renal failure, compared to essential hypertension and control subjects. Plasma angiotensin II was increased in chronic renal failure compared to essential hypertension and controls. Estimated creatinine clearance and nightly blood pressure dips were inversely correlated in essential and secondary hypertension, i.e. with a decreasing renal function both systolic and diastolic nightly blood pressure dips were gradually attenuated. In the whole group of patients the nightly systolic and diastolic blood pressure dips were negatively correlated to basal plasma renin activity, plasma aldosterone and atrial natriuretic peptide levels, i.e. the higher the basal plasma hormone level the lower the blood pressure dip. In conclusion, patients with essential hypertension have elevated but normally configured 24-h blood pressure profiles, and patients with different kinds of secondary hypertension have elevated 24-h blood pressure profiles and attenuated nightly systolic and diastolic blood pressure falls. The more the renal function is reduced and the more the plasma levels of renin and aldosterone are increased, the more the nocturnal fall in blood pressure is reduced. It is suggested that the attenuated or absent decrease in nocturnal blood pressure in secondary renal hypertension is caused by an abnormally increased secretion of vasoactive hormones and/or by so far unknown factors released from the diseased kidney.     

Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis

BACKGROUND & AIMS: Therapeutic paracentesis may be associated with a circulatory dysfunction, manifested by a marked increase of the plasma renin activity and plasma norepinephrine. The aim of the study was to characterize the systemic and hepatic hemodynamic changes associated with paracentesis-induced circulatory dysfunction. METHODS: Changes in plasma renin, aldosterone, and norepinephrine, and in systemic and hepatic hemodynamics were assessed 1 hour and 6 days after complete mobilization of ascites in 37 patients treated by total paracentesis plus intravenous dextran-70 infusion. RESULTS: Paracentesis-induced circulatory dysfunction occurred in 10 patients (renin and norepinephrine increased from 9.0 +/- 10.5 to 28.8 +/- 19.0 ng.mL-1.h-1 and from 752.0 +/- 364.0 to 1223.0 +/- 294.0 pg/mL, respectively) and was associated with significant reduction in systemic vascular resistance (-13.0% +/- 2.6%; P < 0.05) and increase in hepatic venous pressure gradient (from 19.5 +/- 1.5 to 22.5 +/- 2.4 mm Hg; P < 0.01). In the remaining 27 patients, mobilization of ascites also induced a significant but smaller reduction in systemic vascular resistance (-5.0% +/- 1.6%; P < 0.05) without significant changes in renin, norepinephrine, and hepatic venous pressure gradient. CONCLUSIONS: Paracentesis-induced circulatory dysfunction is predominantly caused by an accentuation of the arteriolar vasodilation already present in untreated cirrhotic patients with ascites. The homeostatic activation of endogenous vasoactive systems may account for the increased intrahepatic vascular resistance associated with this condition.     

Principal component analysis of the elongation of metacarpal and phalangeal bones

The cholesterol-lowering effect of portacaval anastomosis in homozygous familial hypercholesterolemia suggested a study of lipid metabolism in cirrhotic patients after portasystemic anastomoses. Fasting serum cholesterol, triglycerides, insulin, and glucagon levels were obtained in 20 patients with alcoholic cirrhosis and portacaval anastomosis, and in 21 nonshunted subjects with cirrhosis. After 100 g of glucose, given orally, insulin and glucagon levels were measured. In the shunted patients serum cholesterol was higher than in the nonshunted subjects, 240 +/- 15 mg per 100 ml (mean +/- 1 SEM) versus 180 +/- 13 mg per 100 ml, P less than 0.01. Triglycerides were normal in both groups. Fasting insulin was elevated to a greater extent in the shunted patients with cirrhosis (36 +/- 5 muU per ml) than in the nonshunted patients (22 +/- 4 muU per ml), P less than 0.05. Two hours after glucose, insulin levels were also elevated to a greater extent in the shunted subjects (304 +/- 50 muU per ml) than in the nonshunted subjects (167 +/- 29 muU per ml), P less than 0.03. Fasting glucagon (corrected for interference factor) was elevated to a greater extent in the shunted subjects (204 +/- 35 pg per ml) than in the nonshunted subjects (80 +/- 19 pg per ml), P less than 0.01. The explanation for serum cholesterol elevation after surgical shunting in cirrhotics is unknown. Two possible hypotheses--the differential action of insulin and glucagon on cholesterol metabolism and the effects of shunting on the cirrhotic liver--are discussed.     

Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study Group

Thrombotic complications of pulmonary circulation occur in patients with chronic obstructive pulmonary disease (COPD). In the present study, we sought to evaluate in vivo platelet activation through the measurement of 11/dehydro-thromboxane (Tx) B2 TxA2 major metabolite in the urine, in 29 patients with COPD, compared with 29 sex- and age-matched healthy subjects. The urinary excretion of 11-dehydro-TxB2 was significantly higher in patients with COPD than in control subjects: median (range), 753 (277-4,409) and 275 (129-612) pg/mg creatinine, respectively; p < 0.0001). Moreover, 11-dehydro-TxB2 excretion was inversely related with arterial oxygen tension (rho = -0.46; p = 0.0145). In five of the 29 patients a short-term therapeutic course with oxygen supplementation induced a significant decrease of urinary 11-dehydro-TxB2 excretion: median range, 941 (452-2,640) to 445 (166-1,560) pg/mg creatinine. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin was associated with more than 90% inhibition of thromboxane metabolite excretion, demonstrating its being of platelet origin. Plasma levels of prothrombin fragment F1 + 2 were higher in patients than in control subjects (2.6 +/- 1.5 versus 0.9 +/- 0.4 nM, p = 0.0001). No relation between 11-dehydro-TxB2 excretion and plasma F1 + 2 levels was found. We conclude that platelet TxA2 biosynthesis is enhanced in patients with COPD and may be influenced by arterial oxygen tension changes.