Allopurinol Prevents Cirrhosis-Related Complications: A Quadruple Blind Placebo-Controlled Trial.

BACKGROUND: Complications associated with liver cirrhosis are various and potentially fatal. The treatment options to counteract hepatic decompensation are limited. Therefore, the study aimed to explore the use of allopurinol in preventing the recurrence of liver cirrhosis-related complications. METHODS: One hundred patients with hepatic decompensation were randomized into 1:1 ratio to receive either allopurinol 300 mg or placebo tablets once daily for 6 months. The primary endpoint was the incidence of cirrhosis-related complications (overt ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, and hepatic encephalopathy). RESULTS: Six months following treatment, allopurinol reduced the relative risk (RR) of any first complication experienced after enrollment by 56% (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.27-0.62); P ˂ .001). Allopurinol decreased the RR of overt ascites by 67% (HR 0.33; 95% CI, 0.0098-0.94); P = .039] and reduced the RR of spontaneous bacterial peritonitis by about 75% (HR 0.25; 95% CI, 0.05-0.76; P = .01). Likewise, allopurinol was linked to an 80% reduction in the RR of developing hepatorenal syndrome (HR 0.2; 95% CI, 0.04-0.87; P = .033). CONCLUSION: Allopurinol significantly decreased the recurrence of overall liver cirrhosis-related complications. Therefore, allopurinol may constitute a promising agent for patients with hepatic decompensation. These positive outcomes could be a result of its ability to reduce bacterial translocation and inflammation. GOV IDENTIFIER: NCT005545670.

Prevention of Hepatorenal Insufficiency Associated with Lead Exposure by Hibiscus sabdariffa L. Beverages Using In Vivo Assay.

Lead pollution is a major environmental challenge worldwide. Therefore, dietary interventions that are aimed at preventing lead's deleterious effects on body organs are needed. The study's goal was to study and compare the protective effect of cold and hot beverages of Roselle (Hibiscus sabdariffa L.) red calyces (CRB and HRB, respectively) on liver and kidney insufficiency associated with lead exposure in male rats. Adult albino rats (32 males) were divided into four groups of equal number, including a normal control (group 1), while groups from 2 to 4 received lead acetate (20 mg/kg body weight/day) and were kept untreated (group 2). The 3rd and the 4th groups received CRB and HRB (0.5 ml/100 g body weight/day), respectively, for 6 weeks. The gain in the body and relative weights of the liver and kidneys were calculated. Liver and kidney functions were determined in serum, while lead, delta-aminolevulinic acid dehydratase, and oxidative stress markers were established in tissues. Specimens from the liver and kidney of sacrificed rats were histopathologically examined. The total activity of antioxidants and total content of anthocyanin of both beverages were determined. Lead exposure resulted in its accumulation in tissues, leading to overweight and liver and kidney insufficiency along with oxidative stress, which was further confirmed by histological staining. CRB was more efficient than HRB in preventing the deleterious effects of lead intoxication. Due to their antioxidant properties, the present study proved that Roselle red calyx beverages, particularly the cold ones, are protective agents against lead-associated disorders in a rat model.

Evidence-based protocol for diagnosis and treatment of hepatorenal syndrome is independently associated with lower mortality / El protocolo basado en la evidencia para el diagnóstico y tratamiento del síndrome hepatorrenal se asocia de forma independiente con una menor mortalidad

Background: Hepatorenal syndrome (HRS) is the deadliest complication of cirrhosis. The purpose of this study is to analyze if the use of a protocol for HRS is associated with higher survival in these patients.Methods: An evidence-based protocol for the diagnosis and treatment of HRS was instituted in 2013. Data from medical records from 2010 to 2016 were obtained by searching the hospital database for patients who received terlipressin, in the three years before and after the institution of the protocol. Data were reviewed to confirm the diagnosis of HRS and multiple variables were collected. Liver-specific scores were calculated and a stepwise Cox regression approach was used for univariate and multivariate analysis.Results: The study included 46 patients, 20 from the pre-protocol period and 26 from the post-protocol period. Respectively, mortality at 30 days, 90 days and 365 days was 75%, 75% and 90% for the pre-protocol period, and 61%, 69% and 80% for the post-protocol period. In the multivariate analysis, an aspartate aminotransferase (AST) of <40U/L, the pre-protocol period and higher Child-Turcotte-Pugh scores were associated with higher 30-day and 90-day mortality. The total mean dose of terlipressin and human albumin used per patient was reduced from 27mg to 22mg and from 236g to 144g, respectively, after the institution of the protocol. This was not associated with higher mortality.Conclusion: The use of an evidence-based protocol for the treatment of HRS translated into a higher survival. The authors suggest that the use of evidence-based protocols for the diagnosis and treatment of HRS could reduce cost and mortality in tertiary hospitals.

Antecedentes: El síndrome hepatorrenal (SHR) es la complicación más mortal de la cirrosis. El objetivo de este estudio es analizar si el uso de un protocolo para el SHR se asocia a una mayor supervivencia en estos pacientes.Métodos: En 2013 se instituyó un protocolo basado en la evidencia para el diagnóstico y tratamiento del SHR. Los datos de los registros médicos del 2010 al 2016 se obtuvieron mediante la búsqueda en la base de datos del hospital de pacientes que recibieron terlipresina, 3 años antes y después de la institución del protocolo. Se revisaron los datos para confirmar el diagnóstico de SHR y se recopilaron múltiples variables. Se calcularon las puntuaciones específicas del hígado y se utilizó un enfoque gradual de la regresión de Cox para el análisis univariado y multivariado.Resultados: Se incluyó a 46 pacientes, 20 del período preprotocolo y 26 posprotocolo. Respectivamente, la mortalidad a los 30, 90 y 365 días fue del 75, el 75 y el 90%, respectivamente, para el período previo al protocolo y del61, el 69 y el 80%, respectivamente, para el posterior al protocolo. En el análisis multivariado, aspartato aminotransferasa (AST) <40 U/l, el período preprotocolo y las puntuaciones más altas de Child-Turcotte-Pugh se asociaron con una mayor mortalidad a los 30 y 90 días. Las dosis media total de terlipresina y albúmina humana utilizada por paciente se redujo de 27 a 22mg de terlipresina y de 236 a 144g de albúmina humana después de la institución del protocolo. Esto no se asoció con una mayor mortalidad.Conclusión: El uso de un protocolo basado en la evidencia para el tratamiento del SHR se tradujo en una mayor supervivencia. Los autores sugieren que el uso de protocolos basados en la evidencia para el diagnóstico y tratamiento del SHR podría reducir el costo y la mortalidad en los hospitales de tercer nivel.

The Use of Rifaximin in Patients With Cirrhosis.

Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.

Albumin: Indications in chronic liver disease.

Albumin is currently employed as a plasma expander to prevent and treat specific complications of cirrhosis with ascites, such as the prevention of paracentesis-induced circulatory dysfunction and renal dysfunction induced by spontaneous bacterial peritonitis, as well as the diagnosis and treatment of acute kidney injury and hepatorenal syndrome. Recently, evidence has shown that long-term albumin administration in patients with decompensated cirrhosis reduces mortality and incidence of complications, eases the management of ascites, is cost effective, and has a good safety profile.

Effectiveness of terlipressin for prevention of complications after major liver resection - A randomized placebo-controlled trial.

BACKGROUND: Elevated portal pressure in response to major liver resection is associated with impaired liver regeneration and increased postoperative complications. Terlipressin, a splanchnic vasoconstrictor used for treatment of hepatorenal syndrome, was tested for reduction of complications and renal protection after liver resection. METHODS: A randomized double-blinded placebo-controlled trial including patients undergoing elective major liver resection was performed. Terlipressin was administered to patients in the intervention group for five days. The primary outcome parameter was the incidence of a clinical composite endpoint of following liver specific complications 6 weeks after surgery: liver failure, ascites, bile leakage, intra-abdominal abscess and operative mortality. Postoperative kidney function was assessed as a secondary endpoint. RESULTS: 150 patients (mean age 63.4 years, 73.3% male) were included. No difference was found in the composite endpoint between the placebo and intervention group (32.8% versus 30.8%, relative risk 1.066, 95%CI 0.643 to 1.769, p = 0.85). Patients receiving terlipressin showed a significant lower decrease in postoperative estimated glomerular filtration rate compared to placebo (two way ANOVA, p = 0.005). CONCLUSION: Perioperative administration of terlipressin during major liver surgery did not affect a composite endpoint of liver specific complications, but significantly protected from postoperative deterioration of kidney function compared to placebo. CLINICALTRIALS. GOV IDENTIFIER: NCT01921985.

Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival.

BACKGROUND AND STUDY AIMS: Current guidelines favour albumin administration during spontaneous bacterial peritonitis (SBP). However, its use is limited in clinical practice and low doses are preferred. The aim of our study was to determine the effect of low dose albumin perfusion during SBP on mortality and prevention of hepatorenal syndrome (HRS) in cirrhotic patients. PATIENTS AND METHODS: A retrospective study including consecutive patients with SBP hospitalized from 2002 to 2015 was performed. All patients were treated by intravenous empiric antibiotics associated with albumin infusion (30 g/day the first and third day) irrespective of patient's weight. The diagnosis of HRS was assessed according to the International Ascites Club criteria. The survival, the frequency of HRS and any disturbance in renal function were recorded. RESULTS: Fourty nine patients (sex ratio = 0.81, mean age 60.6 years [23-89]) were included. Main cause of cirrhosis was hepatitis B and C in 42.9% of cases. 63.3% were of Child Pugh C score%. The first line intravenous antibiotic treatment was based on cefotaxime in 87.8% of cases, followed by ofloxacin in 6.1% of cases. The outcome was favourable in 85.7% of cases. HRS was observed in 9 patients (18.3%) within 18 months [1-55]. Otherwise, 10 patients (20.4%) experienced an increase in creatinine level despite of albumin perfusion. The immediate mortality was 4%, and the six months survival was of 81.8%. CONCLUSION: Despite even a low dose administration of albumin during SBP, renal dysfunction and HRS occurred less than described in literature. These results associated with cost considerations could suggest to use such an intervention during SBP or to select high risk patients who must receive albumin perfusion during SBP.

Primary and secondary prophylaxis of spontaneous bacterial peritonitis: current state of the art.

Introduction: Spontaneous bacterial peritonitis represents a frequent and severe complication in cirrhotic patients with ascites. In daily practice, the diagnosis of spontaneous bacterial peritonitis might be challenging in the absence of the typical signs and symptoms of infection such as fever or leukocytosis. Areas covered: Aim of this review is to revise the current state of the art on primary and secondary spontaneous bacterial peritonitis. Literature search in Medline/Pubmed was performed. Expert opinion: Historically, gram-negative bacteria were the most frequent etiologic agents of spontaneous bacterial peritonitis, with Escherichia coli and Klebsiella spp. being the most frequently isolated bacteria. However, major changes in this regard occurred over the last few decades with an increasing prevalence of gram-positive, quinolone-resistant, and multidrug-resistant bacteria. In particular, the increasing prevalence of quinolone-resistant bacteria challenged the prominent role of norfloxacin in spontaneous bacterial peritonitis prevention. Given the high mortality rate and the risk of developing the hepatorenal syndrome, prophylaxis of spontaneous bacterial peritonitis is indicated in three high-risk populations: patients with acute gastrointestinal hemorrhage, patients with low total protein content in ascitic fluid and advanced cirrhosis, and patients with a previous history of spontaneous bacterial peritonitis (secondary prophylaxis).

Role of Probiotic Mixture with and Without Green Tea Extract in Prevention of Hepatorenal Syndrome in Rat Model.

BACKGROUND AND OBJECTIVE: Hepatorenal syndrome (HRS) is a major public health problem in which both liver and kidney dysfunctions are encountered. The present research aimed to investigate the beneficial use of micro-encapsulated probiotic alone (Bifidobacterium bifidum, Lactobacillus delbrueckii and Streptococcus thermophilus mixture) or with green tea alcohol extract in HRS model in rats. MATERIALS AND METHODS: Flavonoids content and in vitro antioxidant activity of the extract were assessed. The animal experiment consisted of 4 groups; control healthy, control with HRS and two test groups with HRS and treated with either the encapsulated probiotic mixture alone or with green tea extract. After 3 weeks; urinary creatinine was determined in 24 h rat urine samples. Colonic microbiota was assessed in faeces. Plasma malondialdehyde, nitrite, C-reactive protein, creatinine, uric acid, urea and the activity of transaminases, catalase (CAT) and angiotensin-1 converting enzyme (ACE-1) were determined with calculation of creatinine clearance. RESULTS: Results showed significant increase in all biochemical parameters of HRS control except for ACE-1, CAT and creatinine clearance that experienced significant reduction along with dysbiosis compared to healthy control. Test groups showed improvement in all biochemical parameters with superiority to probiotic-green tea extract combination. Both treatments produced significant increase in fecal B. bifidum, S. thermophilus and L. bulgaricus and reduction of Staphylococci and Coliform. The effect of probiotic-green tea extract combination was more pronounced concerning the last three. Flavonoids and antioxidant activity of the extract were 1.325±0.01 mg quercetin/g and 98±1.66%, respectively. CONCLUSION: Administration of micro-encapsulated probiotic with or without alcohol green tea extract exerted significant prevention of HRS in rat with superiority to probiotic-green tea extract combination.

Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome.

BACKGROUND: Hepatorenal syndrome (HRS) is a severe complication of liver cirrhosis, with poor survival. Rifaximin is a gut-selective broad-spectrum antibiotic. AIM: The aim of this study was to evaluate the role of rifaximin as a primary prevention of HRS. PATIENTS AND METHODS: Eighty patients with liver cirrhosis and ascites were enrolled. They were randomized into two groups: control (n=40) and rifaximin group (n=40). Baseline liver function tests, renal function tests, complete blood count, international normalized ratio, urine analysis, and abdominal ultrasonography were carried out. Rifaximin 550 mg was administered twice daily for 12 weeks. Renal functions were measured every 4 weeks with monitoring of HRS occurrence and possible precipitating factor. RESULTS: Both groups were matched for age, sex, virology, serum bilirubin, serum albumin, aspartate aminotransferase, alanine aminotransferase, hemoglobin, white blood cells, platelets, international normalized ratio, potassium, and Child-Pugh score. In contrast to the rifaximin group, the control group showed statistically significant serial blood urea nitrogen (18.84±7.17, 19.85±6.10, 21.54±4.79, and 22.96±5.82 mg/dl; P=0.001) and serum creatinine (0.94±0.25, 1.02±0.24, 1.12±0.16, and 1.21±0.17 mg/dl; P=0.001) levels. The overall blood urea nitrogen and serum creatinine change was statistically higher in the control group than the rifaximin group (20.8 vs. 18.24 mg/dl and 1.07 vs. 0.99 mg/dl, respectively). HRS developed more in the control group than the rifaximin group [9 (22.5%) vs. 2 (5%); P=0.048]. In both groups, HRS was precipitated by spontaneous bacterial peritonitis mainly and large volume paracentesis. The Child-Pugh score, control group, baseline serum sodium, and creatinine were predictors of HRS. CONCLUSION: Rifaximin may be useful as a primary prevention of HRS.

Rifaximin for the prevention of spontaneous bacterial peritonitis and hepatorenal syndrome in cirrhosis: a systematic review and meta-analysis.

Prophylactic antibiotics have been recommended in patients with a previous history of spontaneous bacterial peritonitis (SBP). Recently, there has been interest in the use of rifaximin for the prevention of SBP and hepatorenal syndrome (HRS). We conducted a meta-analysis to evaluate this association of rifaximin. We searched several databases from inception through 24 January 2017, to identify comparative studies evaluating the effect of rifaximin on the occurrence of SBP and HRS. We performed predetermined subgroup analyses based on the type of control group, design of the study, and type of prophylaxis. Pooled odds ratios (ORs) were calculated using a random effects model. We included 13 studies with 1703 patients in the meta-analysis of SBP prevention. Pooled OR [95% confidence interval (CI)] was 0.40 (95% CI: 0.22-0.73) (I=58%). On sensitivity analysis, adjusted OR was 0.29 (95% CI: 0.20-0.44) (I=0%). The results of the subgroup analysis based on type of control was as follows: in the quinolone group, pooled OR was 0.42 (95% CI: 0.14-1.25) (I=55%), and in the no antibiotic group, pooled OR was 0.40 (95% CI: 0.18-0.86) (I=64%). However, with sensitivity analysis, benefit of rifaximin was demonstrable; pooled ORs were 0.32 (95% CI: 0.17-0.63) (I=0%) and 0.28 (95% CI: 0.17-0.45) (I=0%) for the comparison with quinolones and no antibiotics, respectively. Pooled OR based on randomized controlled trials was 0.41 (95% CI: 0.22-0.75) (I=13%). For the prevention of HRS, the pooled OR was 0.25 (95% CI: 0.13-0.50) (I=0%). Rifaximin has a protective effect against the development of SBP in cirrhosis. However, the quality of the evidence as per the GRADE framework was very low. Rifaximin appeared effective for the prevention of HRS.

Deoxyribonuclease partially ameliorates thioacetamide-induced hepatorenal injury.

Several recent studies have shown that liver injury is associated with the release of DNA from hepatocytes. This DNA stimulates innate immunity and induces sterile inflammation, exacerbating liver damage. Similar mechanisms have been described for acute renal injury. Deoxyribonuclease degrades cell-free DNA and can potentially prevent some of the induced tissue damage. This study analyzed the effects of thioacetamide-induced hepatorenal injury on plasma DNA in rats. Plasma DNA of both nuclear and mitochondrial origin was higher in thioacetamide-treated animals. Administration of deoxyribonuclease resulted in a mild, nonsignificant decrease in total plasma DNA and plasma DNA of mitochondrial origin but not of nuclear origin. This was accompanied by a decrease in bilirubin, creatinine, and blood urea nitrogen as markers of renal function. In conclusion, the study confirmed the hepatotoxic and nephrotoxic effect of thioacetamide. The associated increase in cell-free DNA seems to be involved in hepatorenal pathogenesis because treatment with deoxyribonuclease resulted in a partial prevention of hepatorenal injury. Further experiments will focus on the effects of long-term treatment with deoxyribonuclease in other clinically more relevant models. Clinical studies should test endogenous deoxyribonuclease activity as a potential risk determinant for kidney or liver failure.NEW & NOTEWORTHY Thioacetamide-induced hepatorenal injury resulted in higher plasma cell-free DNA. Deoxyribonuclease decreased average cell-free DNA of mitochondrial origin but not nuclear origin. Deoxyribonuclease partially prevented hepatorenal injury in rats.

Hepatorenal Syndrome: Diagnosis and Treatment - newsreel.

Hepatorenal syndrome (HRS) is defined as renal failure that occurs in the presence of severe acute or chronic liver disease in the absence of underlying renal pathology. Due to the functional nature of the disease and the absence of specific diagnostic markers, HRS diagnosis is determined based on positive criteria associated with excluding other causes of renal failure in patients with liver cirrhosis and ascites. Differentiation from other types of acute or chronic renal disease is extremely difficult and therapeutic options are limited, prophylactic behavior is most appropriate in patients with severe hepatic disease and risk factors for the installation of hepatorenal syndrome. Highlighting all precipitating factors of acute renal insufficiency and therapeutic modalities in order to minimize adverse events is an important step in improving the follow-up of the patients with liver cirrhosis. The prognosis is reserved especially for type 1 HRS. Liver transplantation is the best option for patients without contraindications. The therapies introduced in recent years, such as vasoconstrictor drugs or transjugular intrahepatic portosystemic shunt are effective methods in the renal function improvement.

Effect of different therapeutic modalities on systemic, renal, and hepatic hemodynamics and short-term outcomes in cirrhotic patients with spontaneous bacterial peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a major risk factor for hepatorenal syndrome. Albumin infusion has been shown to prevent renal impairment and reduce mortality in SBP. The study aimed to compare the effect of different therapeutic modalities on hemodynamics and short clinical outcomes in high-risk patients with SBP. METHODS: Two hundred cirrhotic patients with SBP and bilirubin greater than 4 mg[Fraction Slash]dl or creatinine more than 1 mg[Fraction Slash]dl were enrolled. Patients were randomized to receive albumin, terlipressin, low-dose albumin plus terlipressin, or midodrine. Systemic, renal, and hepatic hemodynamics were estimated at baseline, 3, and 10 days of treatment. Renal impairment was diagnosed when the blood urea nitrogen or serum creatinine levels increased by more than 50% of the pretreatment value. RESULTS: SBP resolved in most of patients in all groups (P>0.05). Cardiac output and portal flow decreased, whereas systemic vascular resistance increased significantly in terlipressin and albumin plus terlipressin groups compared with the albumin group after 3 and 10 days. After 10 days, plasma renin activity, renal, and hepatic arteries resistive index were significantly higher in the midodrine group compared with the albumin group. The midodrine group did not show any significant changes in the heart rate, mean arterial pressure, cardiac output, and portal blood flow compared with the albumin group after 3 or 10 days. There was no significant difference in renal impairment or mortality between any of the groups. CONCLUSION: Terlipressin and low-dose albumin plus terlipressin could be used as a therapeutic alternative to standard-dose albumin in high-risk SBP patients.

AISF-SIMTI Position Paper: The appropriate use of albumin in patients with liver cirrhosis.

The use of human albumin is common in hepatology since international scientific societies support its administration to treat or prevent severe complications of cirrhosis, such as the prevention of post-paracentesis circulatory dysfunction after large-volume paracentesis and renal failure induced by spontaneous bacterial peritonitis, and the treatment of hepatorenal syndrome in association with vasoconstrictors. However, these indications are often disregarded, mainly because the high cost of human albumin leads health authorities and hospital administrations to restrict its use. On the other hand, physicians often prescribe human albumin in patients with advanced cirrhosis for indications that are not supported by solid scientific evidence and/or are still under investigation in clinical trials. In order to implement appropriate prescription of human albumin and to avoid its futile use, the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) nominated a panel of experts, who reviewed the available clinical literature and produced practical clinical recommendations for the use of human albumin in patients with cirrhosis.

[Is there a role for pentoxifylline in the treatment of alcoholic hepatitis?]. / ¿Tiene algún papel la pentoxifilina en el tratamiento de la hepatitis alcohólica?

Despite better knowledge of the pathogenesis of severe alcoholic hepatitis (AH), corticosteroids are still the treatment recommended by clinical guidelines, pentoxifylline being the second-line option for non-responders to corticosteriods and for patients with contraindications. Pentoxifylline is a phosphodiesterase inhibitor with an anti-TNF effect and has been reported to reduce mortality and the incidence of hepatorenal syndrome in severe AH. After the first report, several studies, of distinct quality, have tested the efficacy of pentoxifylline in different scenarios. The conclusions of these studies are that pentoxifylline seems to improve survival in comparison to placebo but has lower efficacy than corticosteroids, with no improvement in survival when added to corticosteroids or in non-responders to steroid therapy. The role of pentoxifylline in severe alcoholic hepatitis is even more doubtful after the results of a very recent controlled study that showed no beneficial effect on survival at 1, 3 and 12 months of follow up, although a very recent network meta-analysis reported a beneficial effect of pentoxifylline alone or with corticosteroids on short-term survival. In conclusion, pentoxifylline has no clear beneficial effects in severe AH but could perhaps be used in patients with a contraindication to corticosteroids. However, the recommendations of clinical guidelines should be reconsidered and it is essential to search for new therapeutic targets for this disease.

[Critically ill patients with decompensated liver cirrhosis - New aspects and intensive care management]. / Dekompensierte Leberzirrhose: intensivmedizinische Aspekte.

The prevalence of liver cirrhosis in the German population is about 1 %. Clinically, compensated liver cirrhosis should be distinguished from decompensated cirrhosis with poor prognosis. Decompensated cirrhosis is defined by the occurrence of complications and consequences of portal hypertension (such as ascites, variceal bleeding, hepatic encephalopathy and hepatorenal syndrome) and progressive liver failure. Optimizing the management of these patients in the intensive care unit could essentially improve their outcome.

Treatment with metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis.

BACKGROUND & AIM: Despite treatment with glucocorticoids, mortality remains high in patients with severe alcoholic hepatitis. Oxidative stress and depletion of mitochondrial glutathione are implicated factors in liver injury. The aim of this study was to evaluate the impact of the addition of metadoxine, a drug which possesses a multifactorial mechanism of action, including antioxidant properties, to standard treatment with glucocorticoids in patients with severe alcoholic hepatitis. MATERIAL AND METHODS: This randomized open label clinical trial was performed in Mexico's General Hospital (Registry Key DIC/10/107/03/043). We randomized 70 patients with severe alcoholic hepatitis. The first group received prednisone (40 mg/day), and the second group received prednisone (40 mg/day) plus metadoxine tablets (500 mg three times daily). The duration of treatment in both groups was 30 days. Survival at 30 and 90 days, development of complications, adverse events and response to treatment (Lille model) were assessed. RESULTS: In the group receiving metadoxine, significant improvements were observed, as follows: survival at 30 days (74.3 vs. 45.7%, P = 0.02); survival at 90 days (68.6 vs. 20.0%, P = 0.0001). There was less development or progression of encephalopathy (28.6 vs. 60.0%, P = 0.008) and hepatorenal syndrome (31.4 vs. 54.3%, P = 0.05), and the response to treatment (Lille model) was higher in the metadoxine group (0.38 vs. 0.63, P = 0.001; 95% CI 0.11 to 0.40). There were no differences between groups regarding the development or progression of variceal hemorrhage or infection. The incidence of adverse events, mainly gastrointestinal, was similar in both groups. CONCLUSIONS: Addition of metadoxine to glucocorticoid treatment improves the short-term survival of patients with severe alcoholic hepatitis and diminishes the development or progression of encephalopathy and hepatorenal syndrome.

Prognosis and treatment of patients with acute alcoholic hepatitis.

Despite alcoholic hepatitis (AH) is the most acute manifestation of alcohol-related liver disease, its treatment remains controversial. Corticosteroids, given either as monotherapy or together with N-acetylecysteine, have been associated with a moderate short-term survival benefit in patients with severe disease. The Maddrey's discriminant function; Glasgow alcoholic hepatitis score; age, bilirubin, INR and creatinine score; and the Model for end-stage liver disease have been proposed for stratifying prognosis in AH enabling selection of the patients to treat. Definition of treatment non-responders using the Lille model after 7 days of therapy may prevent a detrimental impact of prolonged corticosteroids. Pentoxifylline is an effective alternative reducing the occurrence of hepatorenal syndrome. Emerging evidence supports use of liver transplantation in a strictly selected subset of corticosteroid non-responders.

Human serum albumin, systemic inflammation, and cirrhosis.

Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction, prevention of type-1 HRS associated with bacterial infections, and treatment of type-1 hepatorenal syndrome are the main indications. In these indications treatment with HSA is associated with improvement in survival. Albumin is a stable and very flexible molecule with a heart shape, 585 residues, and three domains of similar size, each one containing two sub-domains. Many of the physiological functions of HSA rely on its ability to bind an extremely wide range of endogenous and exogenous ligands, to increase their solubility in plasma, to transport them to specific tissues and organs, or to dispose of them when they are toxic. The chemical structure of albumin can be altered by some specific processes (oxidation, glycation) leading to rapid clearance and catabolism. An outstanding feature of HSA is its capacity to bind lipopolysaccharide and other bacterial products (lipoteichoic acid and peptidoglycan), reactive oxygen species, nitric oxide and other nitrogen reactive species, and prostaglandins. Binding to NO and prostaglandins are reversible, so they can be transferred to other molecules at different sites from their synthesis. Through these functions, HSA modulates the inflammatory reaction. Decompensated cirrhosis is a disease associated systemic inflammation, which plays an important role in the pathogenesis of organ or system dysfunction/failure. Although, the beneficial effects of HAS have been traditionally attributed to plasma volume expansion, they could also relate to its effects modulating systemic and organ inflammation.