Agent In Cirrhosis Research Articles

A Prospective Study on the Clinical Significance of Infections in a Hospital Setting Among the Cirrhotic Patients and Their Outcomes.

Aim and objectives The infection of microbial agents in cirrhosis has increased due to poor immunity, which increases morbidities and mortalities worldwide. The present study aimed to assess the incidence, the type of infections, the pattern of resistance, and the course of hospitalization among cirrhotic patients in the Eastern coastal region. Methodology The study was a descriptive cross-sectional study, and the current study was undertaken for 24 months at the Department of Gastroenterology and Hepatobiliary Sciences, IMS, and SUM. Hospital, Bhubaneswar. Consecutive cirrhotic patients admitted with bacterial infection were prospectively evaluated, and the infection patterns were accessed. The data were collected in a well-structured proforma designed by our study team. Results Out of the total 200 cases, a fraction of 72.5% of males outnumbered the females; the mean age of presentation was 59 ± 12 years. A fraction of 59% of cases had the habit of consuming alcohol which amounted to the predominant etiological factor for cirrhosis, followed by non-alcoholic steatohepatitis (NASH). Urinary tract infection (UTI) and spontaneous bacterial peritonitis (SBP) were more common types of infections in the healthcare-associated (HCA) group; however, pneumonia and skin and soft tissue infections (SSTI) were predominant types of infections in community-acquired (CA) group. The model for end-stage liver disease (MELD) scores were not significantly different amongst the three groups with infections at the time of Diagnosis infection and at the time of hospitalization. However, the MELD scores were substantially higher at the time of infection diagnosis than the MELD scores at the time of admission amongst the three groups with infection. Conclusion The present study showed that infections in cirrhosis were relatively common. Due to increasing resistance patterns, the judicious usage of antibiotics in cirrhosis could be the need of the hour.

Prevention of Cirrhosis Complications: Looking for Potential Disease Modifying Agents.

The current therapeutic strategies for the management of patients with cirrhosis rely on the prevention or treatment of specific complications. The removal of the causative agents (i.e., viruses or alcohol) prevents decompensation in the vast majority of patients with compensated cirrhosis. In contrast, even when etiological treatment has been effective, a significant proportion of patients with decompensated cirrhosis remains at risk of further disease progression. Therefore, therapies targeting specific key points in the complex pathophysiological cascade of decompensated cirrhosis could represent a new approach for the management of these severely ill patients. Some of the interventions currently employed for treating or preventing specific complications of cirrhosis or used in other diseases (i.e., poorly absorbable oral antibiotics, statins, albumin) have been proposed as potential disease-modifying agents in cirrhosis (DMAC) since clinical studies have shown their capacity of improving survival. Additional multicenter, large randomized clinical trials are awaited to confirm these promising results. Finally, new drugs able to antagonize key pathophysiological mechanisms are under pre-clinical development or at the initial stages of clinical assessment.

Direct Oral Anticoagulants in Cirrhosis Patients Pose Similar Risks of Bleeding When Compared to Traditional Anticoagulation.

Direct oral anticoagulants (DOAC) are important new anticoagulant therapies that are not well studied in patients with chronic liver disease. The aim of this study was to compare rates of bleeding in cirrhosis patients treated with DOAC (factor Xa inhibitors: rivaroxaban and apixaban) to those in cirrhosis patients treated with traditional anticoagulation (warfarin and low molecular weight heparin). We identified a total of 39 patients with cirrhosis who received anticoagulation therapy over a 3-year period (20 DOAC and 19 traditional anticoagulation) from a research database. Medical records were reviewed to obtain clinical data to compare between the groups. Clinical characteristics between the two groups were similar. There were three documented bleeding events in the traditional anticoagulation group and four bleeding events in the DOAC group (p=0.9). There were two major bleeding events in the traditional anticoagulation group and one major bleeding event in the DOAC group. There were no documented reports of drug-induced liver injury during this study period. Among all patients, no significant predictors of bleeding were identified using univariate regression and Cox proportional hazard modeling. This is the first clinical study evaluating the use of DOAC in patients with cirrhosis. DOAC display similar safety characteristics when compared to traditional anticoagulation in patients with cirrhosis and are potentially attractive agents for anticoagulation therapy. Larger studies are now needed to better understand the safety and efficacy of these agents in cirrhosis.

Serotypes and Genotypes of the Hepatitis B Virus in Latin America

The World Health Organization has estimated that 2 billion persons are infected with the hepatitis B virus (HBV) with 360 million persons chronically affected. Worldwide, HBV is the causal agent of cirrhosis (30%) and hepatocellular carcinoma (50%). Methods of transmission for HBV are prenatal, percutaneous, and sexual. HBV genotypes, subgenotypes, and subtypes represent genetically stable viral populations that share a separate evolutionary history. Additional instable changes arising from mutations and mutant selection have been observed; these viral subpopulations are HBV variants with medical treatment relevance. Expression of the subtype renders antigenically diverse strains. The same region contains an unknown number of epitopes that define the so-called “a” determinant. Thus, we have two mutually exclusive determinants (d/y, w/r) Review Article Annual Research & Review in Biology, 4(8): 1307-1318, 2014 1308 with four variants (w1 w4 and the expression of a third, q). The difference in 8% of the HBV genome produces different viral groups. Currently, there are ten of these groups (genotypes) classified from A to J, with different geographic distributions. Multiethnic populations present several genotypes and variability is increasing because there are reports of subgenotypes and recombinant intergenotypes, which render the design of effective drugs to combat and eliminate this very difficult virus.

Hyponatremia in cirrhosis: clinical features and management

The presence of dilutional hyponatremia has a poor prognosis for survival in patients with cirrhosis and ascites. Effective and safe treatments are needed to improve prognosis in patients with cirrhosis and dilutional hyponatremia. The initial approach to management includes fluid restriction, low sodium diet, and minimizing the use of diuretics. In addition, the use of hypertonic saline should be avoided in patients with cirrhosis and dilutional hyponatremia. Furthermore, patients should be placed on the top of the list for liver transplantation if they are appropriate candidates. Although V2 arginine vasopressin receptor antagonists that selectively enhance solute-free water excretion in patients with cirrhosis seem very promising, two points must be considered in relation to the available data. First, although the results of phase-2 studies are encouraging, the efficacy and safety of these compounds should be further evaluated. Second, the clinical utility of these agents in cirrhosis has only been assessed in short-term studies. The long-term effects of these drugs remain unknown. Future research with these compounds should not only focus on the effects on serum sodium, but also on treatment and prevention of recurrence of ascites. In addition, the possible beneficial effects of these drugs in the prevention of hepatic encephalopathy would be worth studying.

Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis

Background & Aims : An extrahepatic human neutrophil collagenase complementary DNA (matrix metalloprotease-8) cloned in an adenovirus vector was used as a therapeutic agent in cirrhosis. Methods : A high titer of clinical-grade AdMMP8 was obtained. Results : HeLa cells transduced with AdMMP8 expressed recombinant matrix metalloprotease-8 messenger RNA and matrix metalloprotease-8 protein. Matrix metalloprotease-8 in culture sups showed enzymatic activity against native collagen type I, which was inhibited by ethylenediaminetetraacetic acid, 1,10-phenanthroline, and tissue inhibitor of metalloprotease-1. In vivo transduction showed matrix metalloprotease-8 activity, and studies to establish the efficacy of this characterized vector were performed in CCl 4 and bile duct-ligated cirrhotic rats. Transduction with 3 × 10 11 viral particles per kilogram resulted in hepatic detection of both messenger RNA and protein matrix metalloprotease-8. A consistent response in fibrosis reversal was observed in CCl 4 rats. Liver fibrosis in bile duct-ligated cirrhotic animals was decreased in 45%, along with diminished hydroxyproline content, after AdMMP8 treatment. The expression of matrix metalloprotease-2 and matrix metalloprotease-3 was up-regulated in AdMMP8 rats. Free tissue inhibitor of metalloprotease-1, as an indirect measurement of active uncomplexed matrix metalloproteases, was also increased in the AdMMP8 groups. Transforming growth factor-β messenger RNA was diminished, and matrix metalloprotease-9 and hepatocyte growth factor increased. Treatment in both models correlated with improvements in ascites, functional hepatic tests, and gastric varices, indicating diminished intrahepatic blood pressure in animals injected with AdMMP8. Conclusions : Therefore, therapy with the matrix metalloprotease-8 gene is promising for use in a clinical setting.

Effects of xylitol on urea synthesis in patients with cirrhosis of the liver.

In individuals with cirrhosis the normal inhibiting effect of glucose on urea synthesis is lost, probably because of very high concentrations of glucagon. In agreement, glucose does not prevent the inducing effect of glucagon on urea synthesis in normal humans. In contrast, the sugar alcohol, xylitol, prevents the increasing effect of glucagon in normal humans. We, therefore, examined the effect of xylitol on urea synthesis in individuals with cirrhosis and hyperglucagonemia. Urea synthesis, calculated as urinary excretion rate corrected for accumulation in total body water and intestinal loss, was measured during infusion of alanine (2 mmol/[h x kg body wt]) and during infusion of alanine superimposed on infusion of xylitol (0.12 g/[h x kg body wt]) in 8 individuals with biopsy-proven alcoholic cirrhosis. The functional hepatic nitrogen clearance (FHNC), ie, urea synthesis expressed independent of changes in plasma amino acid concentration, was calculated as the slope of the linear relation between the urea synthesis rate and the plasma amino acid concentration. All individuals had elevated basal plasma glucagon concentration (261 +/- 61 ng/L; mean +/- SEM) and a markedly increased response to alanine infusion (1037 +/- 226 ng/L). This was not changed by xylitol. Neither the basal urea synthesis rate (13.2 +/- 2.5 mmol/h) nor the alanine-stimulated urea synthesis rate (76.8 +/- 3.64 mmol/h) was changed by xylitol. FHNC during the infusion of alanine alone was 10.5 +/- 0.9 L/h and did not change during the concomitant infusion of xylitol (10.1 +/- 1.1 L/h). Xylitol reduces neither urea synthesis nor FHNC. The data do not support an important role of xylitol as a nitrogen-sparing agent in cirrhosis.

Mesenteric vasodilator responses in cirrhotic rats: A role for nitric oxide

The contribution of nitric oxide to mesenteric arterial vasodilator responses was investigated in the isolated perfused mesenteric arterial bed of cirrhotic rats (carbon tetrachloride/phenobarbitone; n = 6). Age- matched (n = 9) and phenobarbitone-treated rats (n = 9) served as controls. Responses to the endothelium-dependent dilators acetylcholine and adenosine 5'-triphosphate (ATP) and the smooth muscle dilator (NO donor) sodium nitroprusside were investigated after tone was raised by continuous infusion of methoxamine, before and during infusion of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 30 mumol/L) +/- L-arginine (1 mmol/L). A significant hyporesponsiveness to methoxamine infusion in cirrhotic preparations (P < .05) was not fully corrected by L-NAME. There was no difference in the percentage vasodilator response to acetylcholine in the cirrhotic group compared with controls; L-NAME significantly and reversibly inhibited the dilator response in all groups. ATP elicited dose-dependent vasodilation that, in the absence of L-NAME, did not differ between the groups. By contrast, in the presence of L-NAME, ATP (5 x 10-8 mol) produced pronounced, reversible vasoconstriction only in cirrhotic animals (P < .02). Vasodilatation attributable to sodium nitroprusside (5 x 10-8 mol) was significantly attenuated in cirrhotic rats. The methoxamine data support the concept of mesenteric hyposensitivity to vasoconstrictor agents in cirrhosis that may be at least partly NO mediated. Increased NO activity in smooth muscle leading to decreased guanylate cyclase availability may account for the diminished vasodilator responses to sodium nitroprusside in cirrhotic preparations. The unchanged responsiveness to vasodilatation by acetylcholine (ACh) and the vasoconstriction to ATP observed during NO blockade in cirrhotic animals indicate that mesenteric endothelial NO is unchanged or possibly diminished. (Hepatology 1996 Jan;23(1):130-6)

Mesenteric vasodilator responses in cirrhotic rats: a role for nitric oxide?

The contribution of nitric oxide to mesenteric arterial vasodilator responses was investigated in the isolated perfused mesenteric arterial bed of cirrhotic rats (carbon tetrachloride/phenobarbitone; n = 6). Age-matched (n = 9) and phenobarbitone-treated rats (n = 9) served as controls. Responses to the endothelium-dependent dilators acetylcholine and adenosine 5'-triphosphate (ATP) and the smooth muscle dilator (NO donor) sodium nitroprusside were investigated after tone was raised by continuous infusion of methoxamine, before and during infusion of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 30 mumol/L) +/- L-arginine (1 mmol/L). A significant hyporesponsiveness to methoxamine infusion in cirrhotic preparations (P < .05) was not fully corrected by L-NAME. There was no difference in the percentage vasodilator response to acetylcholine in the cirrhotic group compared with controls; L-NAME significantly and reversibly inhibited the dilator response in all groups. ATP elicited dose-dependent vasodilation that, in the absence of L-NAME, did not differ between the groups. By contrast, in the presence of L-NAME, ATP (5 x 10(-8) mol) produced pronounced, reversible vasoconstriction only in cirrhotic animals (P < .02). Vasodilatation attributable to sodium nitroprusside (5 x 10(-8) mol) was significantly attenuated in cirrhotic rats. The methoxamine data support the concept of mesenteric hyposensitivity to vasoconstrictor agents in cirrhosis that may be at least partly NO mediated. Increased NO activity in smooth muscle leading to decreased guanylate cyclase availability may account for the diminished vasodilator responses to sodium nitroprusside in cirrhotic preparations. The unchanged responsiveness to vasodilatation by acetylcholine (ACh) and the vasoconstriction to ATP observed during NO blockade in cirrhotic animals indicate that mesenteric endothelial NO is unchanged or possibly diminished.

Impaired reactivity of the peripheral vasculature to pressor agents in alcoholic cirrhosis

Background: Studies of the in vivo vascular reactivity of the peripheral circulation to pressor agents in cirrhosis have produced conflicting results, possibly because of changes in mean arterial pressure that make it difficult to clearly separate peripheral and central effects. The aim of the present study was to assess the reactivity of the forearm circulation to pressor agents in vivo without activating central control systems. Methods: Forearm blood flow was measured by venous occlusion strain gauge plethysmography in the basal state and during the infusion of subpressor doses of norepinephrine and angiotensin II into the brachial artery in 10 male patients with well-compensated alcoholic cirrhosis and 10 male age-matched controls. Plasma renin activity and aldosterone and angiotensin II concentrations were assayed. Forearm and systemic sympathetic nervous system activity was estimated using a norepinephrine spillover technique. Results: Basal forearm blood flow, renin angiotensin aldosterone system activity, and forearm sympathetic nervous system activity were similar in both the control and cirrhotic groups. The cirrhotic patients showed an impaired response to both norepinephrine and angiotensin II. Conclusions: There is impaired reactivity of the peripheral vasculature to pressor agents in cirrhosis, indicating that the control of vascular tone is disturbed even in well-compensated cirrhosis.

Current concepts in therapy. The treatment of cirrhosis of the liver.

Cirrhosis implies generalized distortion of the architecture of the liver, with an increase in fibrous tissue, and once this has appeared there is no positive evidence that normal anatomy can be restored. Clinically, nevertheless, some alcoholic patients with cirrhosis do regain normal, or near normal, liver function with time.The treatment of cirrhosis devolves upon the management of the complications of the disease and the prevention of further damage to the liver, which may allow clinical and perhaps anatomic improvement.Prevention of Further Damage to the LiverAlcohol is the commonest known etiologic agent in cirrhosis, and it seems reasonable . . .

Cirrhosis of the liver in infants and children.

ALTHOUGH many papers have appeared on cirrhosis of the liver, there is only scattered information pertaining to this condition in infants and children. Most of the reports have dealt with a particular type or phase of cirrhosis and have included only a few isolated and often unclassified cases. Nevertheless, as more data accumulate, it appears that cirrhosis of the liver is not as uncommon a disease in infants and children as had originally been believed and that there are certain features in regard to etiology, incidence, and pathogenesis which are more or less characteristic of this age group.* The identification of the etiologic agent in cirrhosis is frequently difficult if not impossible. Although Laennec's (portal) cirrhosis is common in adults, it occurs rarely in children. A number of specific factors have so far been recognized as being responsible for cirrhosis in infants and children: Nutritional.—A chronic deficiency of high-quality

CIRRHOSIS OF THE LIVER IN CHILDREN

Cirrhosis of the liver, one of the rarer diseases of childhood, occurs more frequently than is generally recognized. Emphasis in the past has been placed on cases in which autopsy was done; few patients proved to have cirrhosis have been followed clinically for years. The clinical changes observed depend on the extent of the damage to the liver and the consequent reduction of hepatic efficiency. The disease in children usually differs from that in adults only in having a more acute onset and more rapid course. We have studied 20 children with cirrhosis, 13 of whom came to autopsy. Two patients, 5 years and 4 months of age respectively, who were proved by biopsy of the liver to have cirrhosis, have survived three and five years thus far. Studies of hepatic function have been done recently on them (table 1). The identification of the etiologic agent in cirrhosis in human