Miguel A. Serra

Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis.

BACKGROUND/AIMS Upper gastrointestinal (GI) bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. The aim of this study was to determine the independent predictors of morbidity, mortality, and survival after the first episode of GI bleeding in patients with liver cirrhosis. METHODS In a retrospective study of 403 cirrhotic patients who were admitted in the period January 1982 to December 1994 because of a first episode of GI hemorrhage, epidemiological factors, bleeding-related variables and cirrhosis-related variables that may be associated with hepatic and extrahepatic complications, mortality at 48 h and 6 weeks, and survival up to 30 June 1996 were assessed. RESULTS Forty-five percent of patients developed hepatic and/or extrahepatic complications, with a mortality rate of 7.4% at 48 h and 24% at 6 weeks. Renal failure, rebleeding, hepatocellular carcinoma, and hepatic encephalopathy were independent predictors of mortality. The Kaplan-Meier method showed a median survival of 30.9+/-4.5 months (95% confidence interval 22 to 39.7 months). The cumulative percentage of survivors was 60.2% at 1 year, 33.6% at 5 years, and 14% at 10 years. In a Coxs multiple regression analysis, age, hepatic encephalopathy, hepatocellular carcinoma, Child-Pugh grade, and renal failure were independently associated with long-term survival. CONCLUSIONS The first episode of GI bleeding in patients with liver cirrhosis is associated with high morbidity and mortality. Renal failure, rebleeding, hepatocellular carcinoma, and hepatic encephalopathy were independent risk factors for early death.

Serum and ascitic fluid bacterial DNA: A new independent prognostic factor in noninfected patients with cirrhosis

We tested the hypothesis that the presence of bacterial DNA (bactDNA) in ascitic fluid and serum is associated with decreased survival in patients with cirrhosis. In a prospective, multicenter study, we analyzed the clinical evolution of 156 patients with cirrhosis and ascites (first or recurrence) with lower than 250 polymorphonuclear cells (PMN)/μL, negative ascites bacteriological culture, and absence of other bacterial infections being admitted for evaluation of large‐volume paracentesis, according to the presence of bactDNA at admission. Survival, causes of death, and successive hospital admissions were determined during a 12‐month follow‐up period. BactDNA was detected in 48 patients. The most prevalent identified bactDNA corresponded to Escherichia coli (n = 32/48 patients, 66.6%). Patients were followed for 12 months after inclusion and in this period 34 patients died: 16 of 108 (15%) bactDNA negative versus 18 of 48 (38%) bactDNA positive (P = 0.003). The most frequent cause of death was acute‐on‐chronic liver failure in both groups (7/16 and 9/18 in patients without or with bactDNA, respectively), although more prevalent in the first month of follow‐up in patients with presence of bactDNA (0 versus 4/7). When considering patients with model for end‐stage liver disease (MELD) score less than 15, mortality was significantly higher in those with presence of bactDNA. Spontaneous bacterial peritonitis developed similarly in patients with or without bactDNA at admission. Conclusion: The presence of bactDNA in a patient with cirrhosis during an ascitic episode is an indicator of poor prognosis. This fact may be related to the development of acute‐on‐chronic liver failure at short term and does not predict the development of spontaneous bacterial peritonitis. (HEPATOLOGY 2008;48:1924‐1931.)

IL-6 and IL-18 in Blood May Discriminate Cirrhotic Patients With and Without Minimal Hepatic Encephalopathy

Background and Aims Patients with liver cirrhosis may present minimal hepatic encephalopathy (MHE) that can be unveiled using specific neuropsychologic examination. Evaluation of MHE in cirrhotic patients might have prognostic value. The psychometric HE score (PHES) has been recommended as the “gold standard” in the diagnosis of MHE. It has been proposed that critical flicker frequency (CFF) analysis would be useful for easier detection of MHE. It would also be useful to have some peripheral parameter that could reflect the presence of MHE. It has been recently proposed that inflammation-associated alterations and hyperammonemia may cooperate in the induction of hepatic encephalopathy. The aim of the present work was to assess whether there is a correlation between the alterations in parameters reflecting inflammation, hyperammonemia, and the presence of MHE. Methods We have studied in 55 patients with liver cirrhosis and 26 controls the performance in the PHES battery and the CFF, ammonia, and some interleukins (ILs) as inflammatory markers. Results IL-6 and IL-18 were significantly higher (2.5-fold and 2.2-fold, respectively) in patients with MHE than in those without MHE. There were significant correlations between IL-6 or IL-18 levels and PHES score and CFF. Moreover, all patients with MHE had IL-6 levels higher than 11 ng/mL, whereas all patients without MHE had IL-6 levels lower than 11 ng/mL. Conclusions Inflammatory alterations related with IL-6 and IL-18 may contribute to MHE. Serum concentration of IL-6 and IL-18 may be useful to discriminate cirrhotic patients with and without MHE.

Risk Factors for Nonhepatic Surgery in Patients with Cirrhosis

Cirrhosis of the liver appears to have an unfavorable prognosis in the surgical patient. The aim of this study was to determine risk factors for morbidity and mortality in patients with cirrhosis undergoing nonhepatic surgery. We studied 135 patients with liver cirrhosis undergoing nonhepatic procedures and 86 controls matched by age, sex, and preoperative diagnosis. Preoperative, intraoperative, and postoperative variables associated with 30-day mortality and morbidity were assessed by univariate and multivariate analyses. Patients with cirrhosis showed higher blood transfusion requirements, longer length of hospital stay, and a higher number of complications than controls. The mortality rate was 16.3% in cirrhotics and 3.5% in controls. By univariate analysis, the need for transfusions, prothrombin time, and Child-Pugh score were significantly associated with postoperative liver decompensation, whereas duration of surgery, prothrombin time, Child-Pugh score, cirrhosis-related complications, and general complications were significantly associated with mortality. In the multivariate analysis, Child-Pugh score (odds ratio [OR] 24.4; 95% confidence interval [CI] 5.5 to 106); duration of surgery (OR 5; 95% CI 1.2 to 15.6), and postoperative general complications (OR 3.7; 95% CI 3.4 to 6.4) were independent predictors of mortality. Patients with cirrhosis undergoing nonhepatic operations are at significant risk of perioperative complications leading to death. Independent variables associated with perioperative mortality include preoperative Child-Pugh score, the duration of surgery, and the presence of postoperative general complications.

Serum malondialdehyde: possible use for the clinical management of chronic hepatitis C patients

Serum lipid peroxidation products are increased in inflammatory liver disease and, as we previously reported, also in chronic hepatitis C. We have performed a specific assay of malondialdehyde, the reported most abundant product of lipid peroxidation, in serum of twenty four chronic hepatitis C patients, before, during, and after interferon treatment. Liver biopsies were performed in each patient before and after interferon treatment. The results show higher serum malondialdehyde values in chronic hepatitis C patients than healthy subjects (n = 68) before interferon treatment (p < .001). Mean value of serum malondialdehyde levels after interferon treatment was significantly lower than before it (p < .002). Associating the histopathological findings in each of the 48 biopsies performed, with serum malondialdehyde and alanine aminotransferase activity levels, of the sample obtained the same day of biopsy, a much better correspondence with the histopathological severity was observed for malondialdehyde concentration than for alanine aminotransferase activity. These levels decreased significantly after interferon treatment. However, when the patients were grouped in responding (group I; n = 9) and non-responding (group II; n = 15) to interferon treatment, according to the histopathological findings before and after interferon, the values of group I before interferon treatment were significantly higher than group II (p < .03). Thus, a potential predictive value could be ascribed to the serum malondialdehyde levels before interferon treatment in these patients. We propose the utility of the specific assay of malondialdehyde for the clinical management of chronic hepatitis C patients.

Peginterferon Plus Ribavirin and Sustained Virological Response in HCV-Related Cirrhosis: Outcomes and Factors Predicting Response

OBJECTIVES Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.OBJECTIVES:Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.METHODS:Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.RESULTS:Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1–81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353–7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752–5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418–6.927); baseline viral load <6 × 105 (OR=2.597; 95% CI: 1.583–4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26–3.39). No patient with a HCV-RNA decline <1 log10 at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32–5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81–5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546–4). Improved outcome was more evident in responders with less advanced disease at baseline.CONCLUSIONS:SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.

Interferon decreases serum lipid peroxidation products of hepatitis C patients

Thiobarbituric acid reactive substances (TBARS) concentration in serum has been determined in healthy subjects and in patients suffering acute hepatitis and chronic cases of hepatitis C. Treatment with interferon of the chronic active hepatitis C patients, 5 x 10(6) U three times a week during 2 months, led in those patients whose SGPT activity normalized in serum, to a concomitant decrease in serum TBARS content. The possible theoretical involvement of peroxidation and antioxidants in this beneficial effect of interferon in hepatitis C patients is discussed. The results presented confirm the value of TBARS as laboratory test in the management of liver diseases and as a useful tool for the study of pathogenic and/or therapeutic mechanisms of this viral infection.

Accumulation of Symmetric Dimethylarginine in Hepatorenal Syndrome

In patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines and NO are elevated in patients with hepatorenal syndrome (HRS), compared with patients with cirrhosis without renal failure (no-HRS). Plasma levels of NO, ADMA, SDMA, and l-arginine were measured in 11 patients with HRS, seven patients with no-HRS, and six healthy volunteers. SDMA concentration in HRS was higher than in no-HRS and healthy subjects (1.47 ± 0.25 vs. 0.38 ± 0.06 and 0.29 ± 0.04 μM, respectively; P < 0.05). ADMA and NOx concentrations were higher in HRS and no-HRS patients than in healthy subjects (ADMA, 1.20 ± 0.26, 1.11 ± 0.1, and 0.53 ± 0.06 μM, respectively; P < 0.05; NOx, 94 ± 9.1, 95.5 ± 9.54, and 37.67 ± 4.62 μM, respectively; P < 0.05). In patients with HRS there was a positive correlation between serum creatinine and plasma SDMA (r2 = 0.765, P < 0.001) but not between serum creatinine and ADMA or NOx. The results suggest that renal dysfunction is a main determinant of elevated SDMA concentration in HRS. Accumulation of ADMA as a result of impaired hepatic removal may be the causative factor initiating renal vasoconstriction and SDMA retention in the kidney.

Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis

Purpose: To determine the incidence of hepatocellular carcinoma in cirrhosis and to examine the influence of age and sex, and the contribution of etiological factors. Methods: 967 patients with liver cirrhosis and free of hepatocellular carcinoma were enrolled in this longitudinal, retrospective and observational study. Monitoring for hepatocellular carcinoma was scheduled at 3- to 6-month intervals. The mean (±SD) length of follow-up was 60.3 ± 51.7 months (range 6–258). Results: During the observation period, hepatocellular carcinoma developed in 64 patients. The calculated annual incidence was 2.1%. The probability of being free of liver cancer was 92% at 5 years, 80% at 10 years, and 69% at 15 years. Age was the only independent risk factor for the development of malignancy in the multivariate analysis. There were no differences according to male sex, alcohol abuse, and chronic hepatitis B and C virus infection. Conclusions: The annual incidence of hepatocellular carcinoma was 2.1%. These results, although confirming that age is a risk factor for hepatocellular carcinoma in cirrhosis, indicate that alcohol abuse, male sex, and concurrent hepatitis B and C virus infection do not involve a higher risk of developing liver cancer.

Serum metabolic signature of minimal hepatic encephalopathy by (1)H-nuclear magnetic resonance.

Minimal hepatic encephalopathy (MHE) reduces quality of life of cirrhotic patients, predicts overt hepatic encephalopathy, and is associated with poor prognosis. We hypothesized that MHE arises once metabolic alterations derived from the liver reach a particular threshold. Our aim was to assess whether metabolic profiling of serum samples by high-field (1)H-nuclear magnetic resonance spectroscopy ((1)H NMR) and subsequent multivariate analyses would be useful to characterize metabolic perturbations associated with MHE and to identify potential metabolic biomarkers. Metabolic serum profiles from controls (n = 69) and cirrhotic patients without MHE (n = 62) and with MHE (n = 39) were acquired using high field NMR. Supervised modeling of the data provided perfect discrimination between healthy controls and cirrhotic patients and allowed the generation of a predictive model displaying strong discrimination between patients with and without MHE (R(2)Y = 0.68, Q(2)Y = 0.63). MHE patients displayed increased serum concentrations of glucose, lactate, methionine, TMAO, and glycerol, as well as decreased levels of choline, branch amino acids, alanine, glycine, acetoacetate, NAC, and lipid moieties. Serum metabonomics by (1)H NMR offers a useful approach for characterizing underlying metabolic differences between patients with and without MHE. This procedure shows great potential as a diagnostic tool of MHE as it objectively reflects measurable biochemical differences between the patient groups and may facilitate monitoring of both disease progression and effects of therapeutic treatments.