Carlos Terra

Terlipressin and Albumin vs Albumin in Patients With Cirrhosis and Hepatorenal Syndrome : A Randomized Study

BACKGROUND & AIMS Hepatorenal syndrome is common in patients with advanced cirrhosis and constitutes a major problem in liver transplantation. There is no effective medical treatment for hepatorenal syndrome. METHODS Forty-six patients with cirrhosis and hepatorenal syndrome, hospitalized in a tertiary care center, were randomly assigned to receive either terlipressin (1-2 mg/4 hour, intravenously), a vasopressin analogue, and albumin (1 g/kg followed by 20-40 g/day) (n = 23) or albumin alone (n = 23) for a maximum of 15 days. Primary outcomes were improvement of renal function and survival at 3 months. RESULTS Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with 2 patients (8.7%) treated with albumin alone (P = .017). Independent predictive factors of improvement of renal function were baseline urine volume, serum creatinine and leukocyte count, and treatment with terlipressin and albumin. Survival at 3 months was not significantly different between the 2 groups (terlipressin and albumin: 27% vs albumin 19%, P = .7). Independent predictive factors of 3-month survival were baseline model for end-stage liver disease score and improvement of renal function. Cardiovascular complications occurred in 4 patients treated with albumin alone and in 10 patients treated with terlipressin and albumin, yet permanent terlipressin withdrawal was required in only 3 cases. CONCLUSIONS As compared with albumin, treatment with terlipressin and albumin is effective in improving renal function in patients with cirrhosis and hepatorenal syndrome. Further studies with large sample sizes should be performed to test whether the improvement of renal function translates into a survival benefit.

Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome

Terlipressin plus albumin is an effective treatment for type 1 hepatorenal syndrome (HRS), but approximately only half of the patients respond to this therapy. The aim of this study was to assess predictive factors of response to treatment with terlipressin and albumin in patients with type 1 HRS. Thirty‐nine patients with cirrhosis and type 1 HRS were treated prospectively with terlipressin and albumin. Demographic, clinical, and laboratory variables obtained before the initiation of treatment as well as changes in arterial pressure during treatment were analyzed for their predictive value. Response to therapy (reduction in serum creatinine <1.5 mg/dL at the end of treatment) was observed in 18 patients (46%) and was associated with an improvement in circulatory function. Independent predictive factors of response to therapy were baseline serum bilirubin and an increase in mean arterial pressure of ≥5 mm Hg at day 3 of treatment. The cutoff level of serum bilirubin that best predicted response to treatment was 10 mg/dL (area under the receiver operating characteristic curve, 0.77; P < 0.0001; sensitivity, 89%; specificity, 61%). Response rates in patients with serum bilirubin <10 mg/dL or ≥10 mg/dL were 67% and 13%, respectively (P = 0.001). Corresponding values in patients with an increase in mean arterial pressure ≥5 mm Hg or <5 mm Hg at day 3 were 73% and 36%, respectively (P = 0.037). Conclusion: Serum bilirubin and an early increase in arterial pressure predict response to treatment with terlipressin and albumin in type 1 HRS. Alternative treatment strategies to terlipressin and albumin should be investigated for patients with type 1 HRS and low likelihood of response to vasoconstrictor therapy. (HEPATOLOGY 2009.)

Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study

BACKGROUND & AIMS Treatment with albumin in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) prevents renal failure and improves survival. Whether albumin has similar beneficial effects in patients with infections other than SBP is unknown. METHODS One hundred and ten patients with cirrhosis hospitalized for infections other than SBP were randomly assigned to receive antibiotics plus albumin (1.5 g/kgbw at diagnosis and 1 g/kgbw at day 3) (albumin group; n=56) or antibiotics alone (control group; n=54). The primary end point was survival at 3 months. Secondary end points were effects on renal and circulatory function. RESULTS The renal function, as evaluated by differences in changes in serum creatinine and estimated glomerular filtration rate between the two groups, improved in patients treated with albumin. The circulatory function improved significantly in patients treated with albumin, but not in those from the control group. There was a trend for a lower frequency of type 1 hepatorenal syndrome in the albumin group compared to the control group (1 vs. 4 patients, respectively; p=n.s.). Probability of survival at 3 months was not significantly different among the two groups. However, when adjusted for factors with independent prognostic value, treatment with albumin was an independent predictive factor of survival. CONCLUSIONS As compared with standard antibiotic therapy alone, treatment with albumin together with antibiotics has beneficial effects on the renal and circulatory function and shows a potential survival benefit. Further studies with large sample sizes should be performed to confirm these findings.

Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis.

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo‐inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo‐osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by 1H–magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline‐containing compounds, creatine/phosphocreatine, and N‐acetyl‐aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients. (HEPATOLOGY 2004;39:1613‐1622.)

LEFT ventricular function assessed by echocardiography in cirrhosis: Relationship to systemic hemodynamics and renal dysfunction

BACKGROUND & AIMS The current study aimed at assessing the potential role of cardiac abnormalities in the pathogenesis of circulatory and renal dysfunction in cirrhosis. METHODS One hundred and fifty-two patients (34 without ascites, 95 with ascites without renal failure and 21 with hepatorenal syndrome) were evaluated using Doppler echocardiography. In 102 patients, diastolic function was assessed by measuring parameters related to ventricular filling velocity, mitral annulus velocity and left atrial dimensions. Cardiopulmonary pressures were also measured by cardiac catheterization in 54 patients. In 50 additional patients, left ventricular myocardial strain was performed to estimate myocardial contractility and systolic function. RESULTS Grade 1 and 2 diastolic dysfunction was present in 41% and 16% of the patients, respectively. There was no patient with severe grade 3 diastolic dysfunction. Grade 2 diastolic dysfunction was associated with higher cardiopulmonary pressures but values were within the normal limits in all cases. Diastolic dysfunction directly correlated with liver failure but not with the degree of impairment in circulatory and renal function. The proportion of patients without or with grade 1 or 2 diastolic dysfunction was similar in patients with compensated cirrhosis, with ascites without renal failure or with hepatorenal syndrome despite marked differences in the degree of circulatory dysfunction, as indicated by plasma renin activity and noradrenaline concentration. The heart rate and systolic function were normal in all cases. There were no differences between patients without ascites, with ascites without renal failure or with HRS, despite marked differences in the activity of the renin-angiotensin system and sympathetic nervous system. These features indicate an impaired response of cardiac chronotropic and inotropic function to changes in systemic hemodynamics. CONCLUSIONS These data indicates that: (1) diastolic dysfunction is frequent in cirrhosis but in most cases it is of mild degree and does not increase the cardiopulmonary pressure to abnormal levels. This feature, which may be due to the central hypovolemia of cirrhosis, probably accounts for the lack of symptoms associated with this condition. (2) Diastolic dysfunction in cirrhosis is unrelated to circulatory dysfunction, ascites and HRS. (3) In cirrhosis, there is a lack of response of the left ventricular systolic and chronotropic function to peripheral arterial vasodilation and activation of the sympathetic nervous system and this feature is an important contributory factor to the progression of circulatory dysfunction and the pathogenesis of ascites and HRS.

Effects of contrast media on renal function in patients with cirrhosis: A prospective study

Patients with cirrhosis are frequently submitted to radiological procedures that require the administration of contrast media. Contrast media is a well‐known cause of renal failure, particularly in the presence of some predisposing conditions. However, it is not known whether cirrhosis constitutes a risk factor for contrast media–induced renal failure. The aim of this study was to assess the possible nephrotoxicity of contrast media in patients with cirrhosis. In a first protocol, renal function was evaluated with sensitive methods (glomerular filtration rate using iothalamate I 125 clearance and renal plasma flow using iodohippurate I 131 clearance) before and 48 hours after the administration of contrast media in 31 patients with cirrhosis (20 with ascites, 5 with renal failure). Solute‐free water clearance, urine sodium, prostaglandins, and markers of tubular damage were also measured. The administration of contrast media was not associated with significant changes in renal function tests, neither in the whole group of patients nor in patients with ascites or renal failure. Urinary prostaglandin E2 and N‐acetyl‐β‐D‐glucosaminidase increased significantly, but sodium and solute‐free water excretion remained unchanged. In a second protocol, a different series of 60 patients with cirrhosis and renal failure were examined prospectively. No patient had renal failure due to contrast media. Only in 1 patient with septic shock was contrast media a possible contributing factor. In conclusion, the administration of contrast media is not associated with adverse effects on renal function in patients with cirrhosis. Cirrhosis does not appear to be a risk factor for the development of contrast media–induced nephrotoxicity. (HEPATOLOGY 2004;40:646–651.)

Enhanced liver fibrosis panel as a predictor of liver fibrosis in chronic hepatitis C patients.

Background: Evaluation of fibrosis is crucial in the assessment of chronic hepatitis C (CHC). The enhanced liver fibrosis (ELF) is a serological panel including hyaluronic acid (HA), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), and amino-terminal propeptide of type III procollagen (PIIINP) that has shown good results in predicting liver fibrosis in distinct scenarios of chronic liver diseases. Aims: We aimed to assess the performance of ELF on the detection of fibrosis and cirrhosis in a CHC patient cohort and to compare the results of ELF and transient elastography (TE—Fibroscan) using liver biopsy as reference. Patients and Methods: One hundred twenty patients were prospectively evaluated by TE and ELF using an ADVIA Centaur automated system. The ELF score was calculated using the manufacturer’s algorithm. Biopsies were classified according to the METAVIR score. Receiver operator characteristic curve analyses were performed to evaluate the accuracy of ELF and TE. Results: The area under the receiver operator characteristic curve (AUROC) of ELF for the diagnosis of significant fibrosis was 0.81 [95% confidence interval (CI), 0.73-0.87], for advanced fibrosis was 0.82 (95% CI, 0.74-0.88), and for cirrhosis was 0.78 (95% CI, 0.70-0.85). Using the proposed cutoffs, ELF overestimated fibrosis in 66% (81/120) of cases and underestimated in 3% (3/120). We found no statistically significant difference when comparing the AUROC of ELF and TE for diagnosing fibrosis or cirrhosis. Conclusions: ELF panel is a good noninvasive fibrosis marker and showed similar results to TE in CHC patients. However, new cutoff points need to be established to improve its performance on patients with CHC.

Interobserver variability in transient elastography analysis of patients with chronic hepatitis C.

Transient elastography based on liver stiffness measurement is a non‐invasive method to assess hepatic fibrosis. However, interobserver variability has led to controversy over its use in fibrosis evaluation. To evaluate the interobserver variation in transient elastography in chronic hepatitis C.

Prevalence, variability, and outcomes in portal hypertensive colopathy: a study in patients with cirrhosis and paired controls

BACKGROUND Management of portal hypertensive colopathy (PHC) has been challenged by controversial results in its prevalence and clinical relevance. OBJECTIVE To describe the PHC prevalence and to evaluate the variability in diagnosis, the relation to severity of liver disease, and the incidence of severe outcomes. DESIGN Cross-sectional study. SETTING Endoscopic unit of a tertiary-care academic center in Rio de Janeiro, Brazil. PATIENTS Patients with cirrhosis with portal hypertension and controls paired for age and sex. INTERVENTIONS All patients were submitted to standard and image-enhanced colonoscopies, which were recorded in a coded video file and analyzed twice by a blinded endoscopist. MAIN OUTCOME MEASUREMENTS The prevalence of PHC. RESULTS A total of 51 patients with cirrhosis (55% male, mean age 59 years) and 51 healthy controls (43% male, mean age 61 years) were included. The top ranking colonoscopic findings were angiodysplasia-like lesions, nonspecific vascular pattern, red spots, and colorectal varices, all significantly more frequent in patients with cirrhosis compared with controls. PHC prevalence was 71% in patients with cirrhosis. For PHC, interobserver and intraobserver agreement (k values [standard error]) were 0.68 (0.09) and 0.63 (0.10), respectively. Intraobserver agreement for colonoscopic findings was satisfactory. PHC was not related to more severe liver disease or liver stiffness. Only 5 patients developed severe outcomes during follow-up. LIMITATIONS The exclusion of patients with cirrhosis without esophageal varices and the absence of an interobserver agreement analysis by double-blinded endoscopists. CONCLUSION PHC was highly prevalent in patients with cirrhosis, and its diagnostic agreement was satisfactory. PHC is not associated with relevant severe outcomes in a 12-month follow-up.

202 Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo-inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo-osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by (1)H-magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline-containing compounds, creatine/phosphocreatine, and N-acetyl-aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients.