A prognostic model for predicting survival in cirrhosis with ascites.

BACKGROUND/AIMS: Parameters evaluating renal function and systemic hemodynamics are of prognostic significance in cirrhosis with ascites but are rarely used in the evaluation of survival of these patients. The aim of the current study was to develop a prognostic model to estimate survival of patients with cirrhosis and ascites. METHODS: 216 Cirrhotic patients admitted to hospital for the treatment of ascites were evaluated. Thirty-two demographic, clinical and laboratory variables, including parameters assessing liver and renal function and systemic hemodynamics, were analyzed as predictive factors of survival by using a Cox regression model. RESULTS: Four variables had independent prognostic value: renal water excretion, as assessed by measuring diuresis after water load, mean arterial pressure, Child-Pugh class, and serum creatinine. According to these features a prognostic index was calculated that allows to estimate survival in patients with cirrhosis and ascites. The model accurately predicted survival in an independent series of 84 patients with cirrhosis and ascites. CONCLUSION: A prognostic model that uses four easily available variables and predicts prognosis in cirrhotic patients with ascites has been developed. This model may be useful in the evaluation of patients with ascites for liver transplantation.

Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.

BACKGROUND/AIM: Ornipressin, a vasopressin analog with potent splanchnic vasoconstrictor action, has been shown to reverse hepatorenal syndrome. However, its usefulness in clinical practice is limited by frequent ischemic complications. The aim of this study was to assess the efficacy of terlipressin, an analog of vasopressin with a low profile of side effects, plus albumin in this condition. METHODS: Nine consecutive patients with cirrhosis and hepatorenal syndrome were included in a pilot study of terlipressin (0.5-2 mg/4 h i.v.) therapy associated with iv albumin. RESULTS: Treatment (9 days, range 5-15) was associated with a marked reduction of serum creatinine (3.9+/-0.7 to 1.3+/-0.1 mg/dl, p<0.001, mean+/-SE). Reversal of hepatorenal syndrome (reduction of creatinine below 1.5 mg/dl) was observed in seven of the nine patients. There was a remarkable improvement in circulatory function, with an increase in mean arterial pressure (68+/-2 to 80+/-4 mmHg, p<0.05) and suppression of vasoconstrictor systems activity (plasma renin activity and plasma norepinephrine decreased from 23+/-12 ng/ml x h and 1549+/-373 pg/ml to 3.5+/-2 ng/ml x h and 373+/-98 pg/ml, respectively, p<0.01 for both). No patient developed signs of intestinal, myocardial or distal ischemia. CONCLUSIONS: Terlipressin associated with albumin appears to be a safe and effective treatment of hepatorenal syndrome.

Nitric oxide production and inducible nitric oxide synthase expression in peritoneal macrophages of cirrhotic patients.

The present study assessed whether peritoneal macrophages isolated from cirrhotic patients produce nitric oxide (NO) and express NO synthase type II (NOS II) mRNA and protein. Patients with cirrhosis and ascites without peritonitis or with unresolved or resolved spontaneous bacterial peritonitis (SBP) were studied. Following paracentesis, ascites NO(2)(-) + NO(3)(-) content (NOx) was measured. Peritoneal macrophages from ascites were seeded on well plates, and NO(2)(-) in the medium was determined. NOx was higher in patients with unresolved or resolved SBP than in cirrhotic patients without peritonitis. Macrophages of patients with SBP or resolved SBP produced NO(2)(-) after 30 hours in culture, but those obtained from patients without peritonitis did not. Reverse-transcription polymerase chain reaction (RT-PCR) and immunocytochemical analysis revealed the presence of a clear signal for NOS II mRNA and protein in macrophages of SBP patients, regardless of whether or not the infection subsided. Therefore, peritoneal macrophages isolated from cirrhotic patients with unresolved or resolved SBP produce NO and express the NOS II mRNA and protein, suggesting that NOS II may contribute to the control of SBP, or to its associated pathology, in human cirrhosis.

Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.

BACKGROUND: In patients with cirrhosis and spontaneous bacterial peritonitis, renal function frequently becomes impaired. This impairment is probably related to a reduction in effective arterial blood volume and is associated with a high mortality rate. We conducted a study to determine whether plasma volume expansion with intravenous albumin prevents renal impairment and reduces mortality in these patients. METHODS: We randomly assigned 126 patients with cirrhosis and spontaneous bacterial peritonitis to treatment with intravenous cefotaxime (63 patients) or cefotaxime and intravenous albumin (63 patients). Cefotaxime was given daily in dosages that varied according to the serum creatinine level, and albumin was given at a dose of 1.5 g per kilogram of body weight at the time of diagnosis, followed by 1 g per kilogram on day 3. Renal impairment was defined as nonreversible deterioration of renal function during hospitalization. RESULTS: The infection resolved in 59 patients in the cefotaxime group (94 percent) and 62 in the cefotaxime-plus-albumin group (98 percent) (P=0.36). Renal impairment developed in 21 patients in the cefotaxime group (33 percent) and 6 in the cefotaxime-plus-albumin group (10 percent) (P=0.002). Eighteen patients (29 percent) in the cefotaxime group died in the hospital, as compared with 6 (10 percent) in the cefotaxime-plus-albumin group (P=0.01); at three months, the mortality rates were 41 percent (a total of 26 deaths) and 22 percent (a total of 14 deaths), respectively (P=0.03). Patients treated with cefotaxime had higher levels of plasma renin activity than those treated with cefotaxime and albumin; patients with renal impairment had the highest values. CONCLUSIONS: In patients with cirrhosis and spontaneous bacterial peritonitis, treatment with intravenous albumin in addition to an antibiotic reduces the incidence of renal impairment and death in comparison with treatment with an antibiotic alone.

Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems.

Little information exists on the effects of transjugular intrahepatic portosystemic shunts (TIPS) in the management of cirrhotic patients with hepatorenal syndrome (HRS). The current study was aimed to prospectively evaluate the effects of TIPS on renal function and vasoactive systems in patients with type I HRS. Glomerular filtration rate (GFR) (inulin clearance), renal plasma flow (RPF) (para-aminohippurate clearance), plasma renin activity (PRA), aldosterone (ALDO), norepinephrine (NE), and endothelin (ET) were determined in baseline conditions and at different time intervals after TIPS in 7 patients with type I HRS. TIPS induced a marked reduction of portal pressure gradient (PPG) (20 +/- 1 to 10 +/- 1 mm Hg; P < .05). Renal function improved in 6 of the 7 patients. Serum creatinine and blood urea nitrogen (BUN) decreased from 5 +/- 0.8 and 109 +/- 7 to 1.8 +/- 0.4 mg/dL and 56 +/- 11 mg/dL, respectively (P < .05 for both), and GFR and RPF increased from 9 +/- 4 and 103 +/- 33 to 27 +/- 7 mL/min and 233 +/- 40 mL/min, respectively (P < .05 for both), 30 days after TIPS. These beneficial effects on renal function were associated with a significant (P < .05) reduction of PRA (18 +/- 5 to 3 +/- 1 ng/mL x h), ALDO (279 +/- 58 to 99 +/- 56 ng/dL), and NE (1,257 +/- 187 to 612 +/- 197 pg/mL). ET did not change significantly (28 +/- 8 to 27 +/- 11 pg/mL). Mean survival was 4.7 +/- 2 months (0.3-17 months). Three patients remained alive more than 3 months after TIPS insertion. In conclusion, TIPS improves renal function and reduces the activity of the renin-angiotensin and sympathetic nervous systems in cirrhotic patients with type I HRS. Nevertheless, the efficacy of TIPS in the management of these patients should be confirmed in controlled investigations.

Increased cerebrovascular resistance in cirrhotic patients with ascites.

Studies assessing regional hemodynamics in patients with cirrhosis and ascites have shown vasodilation in the splanchnic circulation and vasoconstriction in the renal circulation and in the brachial and femoral artery vascular territories. The aim of this study was to assess the cerebral vascular resistance in cirrhotic patients with ascites. The resistive index in the middle cerebral artery (an index of the cerebral vascular resistance) and in a renal interlobar artery were measured by Doppler ultrasonography in 7 healthy subjects: 13 patients with compensated cirrhosis and 24 patients with ascites (13 with renal failure). The arterial blood pressure and the activity of the renin-angiotensin and sympathetic nervous systems, as estimated by plasma renin activity and plasma norepinephrine concentration, respectively, were also measured. The resistive index in the middle cerebral artery was significantly increased in patients with ascites (0.68 +/- 0.05, mean +/- SD) as compared with patients without ascites (0.60 +/- 0.01, P < .05) and with healthy patients (0.52 +/- 0.01, P < .01). Renal resistive index was also increased in patients with ascites (0.77 +/- 0.01) compared with the other two groups (0.68 +/- 0.02 and 0.62 +/- 0.00, respectively; P < .001). The resistive index in the middle cerebral artery showed a direct correlation with renal resistive index (r = .73, P < .01), plasma renin activity (r = .61, P < .01), and norepinephrine (r = .53, P < .01). The resistive index in the middle cerebral artery showed an inverse correlation with mean arterial pressure (r = -.45, P < .01). These results indicate that in patients with cirrhosis and ascites there is a cerebral vasoconstriction which is probably related with the arterial hypotension and the overactivity of vasoconstrictor systems.

Hepatorenal syndrome.

The hepatorenal syndrome is a severe and common complication of patients with advanced cirrhosis and ascites. It is characterised not only by renal failure but also by marked alterations in systemic haemodynamics. Renal failure is due to a marked hypoperfusion of the kidney secondary to renal vasoconstriction. Although the pathogenesis of hepatorenal syndrome is not completely understood, it is thought to be the extreme manifestation of the underfilling of the arterial circulation secondary to an arterial vasodilation, located mainly in the splanchnic circulation. Recently, a revised definition and diagnostic criteria of hepatorenal syndrome have been proposed. The prognosis of patients with hepatorenal syndrome is very poor. Liver transplantation is the only effective treatment but it is not applicable in most cases due to short survival. New therapies developed during the last years, such as the use of systemic vasoconstrictors or transjugular intra-hepatic portosystemic shunts appear to be promising, but prospective investigations are needed to delineate their real usefulness.

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.

Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.

Hepatorenal syndrome is caused by a marked vasoconstriction of the renal circulation. It is suggested that the renal vasoconstriction is related to an overactivity of vasoconstrictor systems secondary to a vasodilation of the arterial circulation that causes a reduction in effective arterial blood volume. To test this hypothesis, 16 cirrhotic patients with hepatorenal syndrome were treated with a combination of ornipressin, a potent vasoconstrictor agent, and plasma volume expansion with albumin to improve effective arterial blood volume. The combined treatment was administered either for 3 or 15 days (8 patients each), and the effects on renal function, vasoactive systems, and systemic hemodynamics were assessed. The 3-day treatment with ornipressin and albumin was associated with a normalization of the overactivity of renin-angiotensin and sympathetic nervous systems, a marked increase in atrial-natriuretic peptide levels, and only a slight improvement in renal function. However, when ornipressin and albumin were administered for 15 days, a remarkable improvement in renal function was observed, with normalization of serum-creatinine concentration, a marked increase in renal plasma flow and glomerular filtration rate, and a persistent suppression in the activity of vasoconstrictor systems. However, 3 of 8 patients on 15-day therapy treatment had to be discontinued because of ischemic complications. In conclusion, the decrease in effective arterial blood volume and the activation of vasoconstrictor systems play a crucial role in the pathogenesis of hepatorenal syndrome. Although the prolonged administration of ornipressin combined with plasma volume expansion reverses hepatorenal syndrome, this treatment should be used with great caution in clinical practice because of the risk of ischemic complications.

Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis.

BACKGROUND/AIMS: Circulatory abnormalities with activation of vasoconstrictor systems after large-volume paracentesis are generally considered secondary to an increased extravasation of fluid from the intravascular compartment to the extravascular space with subsequent reduction in plasma volume. To test this hypothesis, plasma volume, the transvascular escape rate of albumin, the absolute escape rate of albumin and the activity of vasoconstrictor systems were measured in 25 cirrhotic patients with ascites in baseline conditions and 2 days after total paracentesis with plasma volume expansion. METHODS: Plasma volume and the transvascular escape rate of albumin, the fraction of albumin passing from the intravascular to the extravascular space per unit of time, were assessed through the plasma disappearance curve of radioiodinated human albumin. The absolute escape rate of albumin, the total flux of albumin from intravascular to extravascular space per unit of time, was also calculated. RESULTS: Eight of the 25 patients (32%) developed marked activation of vasoconstrictor systems after paracentesis. In these patients, plasma renin activity and plasma norepinephrine concentration increased from 6.6+/-2 to 23.4+/-11 ng x ml(-1) x h(-1) and 776+/-229 to 989+/-258 pg/ml, respectively (p<0.05). No significant changes in these parameters were found in the remaining 17 patients. The activation of vasoconstrictor systems occurred in the absence of changes in plasma volume (3456+/-276 vs 3476+/-264 ml, NS), transvascular escape rate of albumin (10.4+/-1 vs 10.9+/-2%/h, NS) and absolute escape rate of albumin (9.9+/-1.9 vs 10.5+/-0.7 g/h, NS). CONCLUSIONS: These results do not support a contraction of plasma volume as the mechanism responsible for activation of vasoconstrictor systems after paracentesis. Rather, the activation of vasoconstrictor systems in the absence of changes in plasma volume suggests that paracentesis accentuates the impairment of "effective" blood volume present in cirrhotic patients with ascites.

Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo.

BACKGROUND/AIMS: Diuretic requirements after mobilization of ascites by paracentesis have never been assessed in cirrhosis. It is also unknown whether diuretics increase the incidence of postparacentesis circulatory dysfunction. The aim of this study was to investigate these features and to assess whether measurement of plasma renin activity and aldosterone prior to paracentesis predicts diuretic response after this procedure. METHODS: Thirty-six patients with non-azotemic cirrhosis and ascites treated by total paracentesis plus i.v. albumin were randomly assigned to receive placebo (n=17) or spironolactone 225 mg/day (n=19) immediately after paracentesis and followed-up for 4 weeks. RESULTS: Five patients (three in the placebo and two in the spironolactone group) abandoned the treatment prior to ascites recurrence or the end of the study due to complications or lack of compliance. The analysis was performed in the remaining 31 patients. Ascites recurrence was more common in the placebo group (13 cases, 93%) than in the spironolactone group (3 cases, 18%) (p<0.0001) and occurred within the first 2 weeks of follow-up in more than 50% of patients. Patients developing ascites in the spironolactone group had higher levels of renin (14.1, 20.6, 32.4 ng/ml per h) and aldosterone (120, 149, 288 ng/dl) than those who did not develop ascites (renin: 2.0+/-2.1 ng/ml per h; range 0.1-6.8; aldosterone: 43+/-38 ng/dl; range 4-116). Three patients in the placebo group and two in the spironolactone group developed postparacentesis circulatory dysfunction (defined as an increase in renin at the third day after paracentesis greater than 50% over baseline levels up to a value higher than 4 ng/ml per h). CONCLUSIONS: Patients with cirrhosis treated by paracentesis should receive diuretics immediately after this procedure to prevent early recurrence of ascites. The administration of 225 mg/day of spironolactone is a good empiric treatment for non-azotemic patients with cirrhosis, because it is effective in most cases and does not increase the incidence of postparacentesis circulatory dysfunction. The determination of plasma levels of renin or aldosterone prior to paracentesis predicts the efficacy of spironolactone in the prevention of ascites recurrence.

Urinary endothelin-like immunoreactivity in patients with cirrhosis.

BACKGROUND/AIMS: To investigate a possible relationship between the renal production of endothelin and the presence of renal dysfunction and activation of vasoactive systems in cirrhosis, the urinary excretion and the circulating plasma levels of immunoreactive endothelin (irET) and the plasma levels of vasoactive hormones were measured in 19 healthy subjects, 12 cirrhotic patients without ascites and 39 patients with ascites and different degrees of renal dysfunction. METHODS: The urinary excretion and the circulating levels of irET were assessed after 5 days on a 40 mEq sodium diet and off diuretics. Renal function parameters and the plasma levels of vasoactive hormones were also measured. RESULTS: Patients with and without ascites had similar values of urinary irET as compared with healthy subjects (30+/-3, 31+/-3 and 29+/-2 ng/day, respectively, p>0.10). By contrast, patients with ascites had higher circulating levels of irET (15+/-1.2 pg/ml) than patients without ascites and healthy subjects (11+/-1.6 and 5+/-0.4 pg/ml, p<0.01). In patients with cirrhosis, no correlation was found between urinary irET and circulating irET. Moreover, urinary irET did not correlate with liver tests, serum and urine sodium, glomerular filtration rate or vasoactive substances. Patients with hepatorenal syndrome had similar urinary irET to patients with ascites without hepatorenal syndrome. CONCLUSIONS: Urinary excretion of irET is not increased in cirrhotic patients with ascites and does not correlate with abnormalities in renal function.

[Current treatment of ascites and spontaneous bacterial peritonitis in Spain: analysis of a survey of gastroenterologists and hepatologists]. / Tratamiento actual de la ascitis y la peritonitis bacteriana espontánea en España: análisis de una encuesta distribuida entre gastroenterólogos y hepatólogos.

During the XXII Congress of the Spanish Association for the Study of the Liver a questionnaire was distributed with the aim of describing the current therapeutic attitude of those attending the meeting, concerning two of the most frequent complications of cirrhosis: ascites and spontaneous bacterial peritonitis (SBP). One hundred twelve of the 135 physicians who answered the questionnaire (83%) use to treat tense ascites by therapeutic paracentesis, while 86 physicians (63.7%) managed moderate ascites with diuretics, with spironolactone being the drug most commonly used (n = 117; 87.3%). The most used diuretic schedule for the treatment of ascites was the isolated administration of spironolactone. Frusemide was associated with spironolactone only when moderate or high doses of the latter were found to be insufficient for increasing urinary sodium excretion and eliminating ascites. Following therapeutic paracentesis however, 79 of those surveyed (58.3%) administered a combination of both diuretics on initiation to avoid reaccumulation of ascitic fluid. Sixty-eight of the physicians (50.3%) used transhepatic intrajugular portosystemic shunt in the treatment of refractory ascites. Cefotaxime was the antibiotic most widely used in the treatment of SBP (n = 119; 88%). Most of the physicians surveyed performed prophylaxis of this infection (generally by the oral administration of norfloxacin) in patients with a previous history of SBP (n = 125; 92.6%) or an episode of gastrointestinal hemorrhage (n = 108; 80%) but not in those patients with no previous history of SBP and with low protein concentrations in the ascitic fluid (n = 40; 29.6%). On the appearance of SBP in patients undergoing prophylactic treatment, cefotaxime remained the antibiotic of choice (n = 104; 79%).

Recurrent liver involvement in heatstroke.

We report the case of a young patient who presented two self-limited episodes of acute jaundice that developed immediately following a long distance run. Zone 3 necrosis was the most prominent histologic change of the liver during the second episode. The diagnosis of heatstroke with liver damage was based on the exclusion of known causes of acute hepatitis, the histopathologic changes and the circumstances preceding the onset of liver disease. This seems to be the first case of severe and recurrent liver impairment due to heatstroke.

[Pleural empyema caused by Cryptococcus neoformans in a patient with liver cirrhosis]. / Empiema pleural por Criptococcus neoformans en una paciente con cirrosis hepática.

Gram negative infections, particularly by E. coli, are usually observed in cirrhotic patients while infections by Cryptococcus neoformans are commonly found in immunosuppressed patients. The case of a cirrhotic patient with hepatitis C virus infection who developed pleural infection by C. neoformans is presented. No disease other than cirrhosis was observed in the patient. The treatment with oral fluconazole was initiated with good clinical response and infection cure. The efficacy of fluconazole in infections by this microorganism has been reported in other cases, mainly in patients with acquired immunodeficiency syndrome. The fact that the patient may be a liver transplant candidate, given the hepatic cirrhosis, leads to speculation as to the need for chronic treatment with fluconazole to avoid reactivation of C. neoformans on initiation of pharmacologic immunosuppression.