eplerenone and Liver-Cirrhosis

The present study was conducted to compare the efficacy and side effects of Spironolactone and Eplerenone in management of ascites due to liver cirrhosis.. 105 patients of ascites with liver cirrhosis were randomized into three groups of 35 patients each. Group I was given Spironolactone 100 mg, group II was given Eplerenone 100 mg and group III was given Eplerenone 50 mg. All patients were put on salt-restricted diet (less than or equal to 2 g of sodium) and no loop diuretics were used. Patients were followed after 7 days from the baseline and then biweekly for the period of three months and serial measurements of weight, abdominal girth and incidence of side effects especially gynecomastia, mastalgia, hyperkalemia were recorded. Results were compared. Patients having Child-Turcotte-Pugh score-C, massive ascites, hepatic encephalopathy, Hepatorenal syndrome and ascites due to cardiac, renal, malignant causes were excluded.. Difference in mean weight reduction was non significant (P = 0.964) in group I and group II whereas the difference was significant when comparison was made between Group I and III; and Group II and III (P = <0.001, <0.001, respectively). In group I, the incidence of gynecomastia was 14.28% whereas in group II and group III no case of gynecomastia was observed (P <0.001, <0.001). Hyperkalemia was present in one patient (2.8%) in group I whereas no patient developed hyperkalemia in group II and group III (P = >0.05, >0.05).. Eplerenone and spironolactone are equally effective in management of ascites due to liver cirrhosis but side effect profile of eplerenone scores over Spironolactone.

Topics: Adult; Aged; Ascites; Diet, Sodium-Restricted; Eplerenone; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

The mineralocorticoid receptor (MR) contributes to fibrosis in various tissues, and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists in hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MRs and eplerenone in cirrhosis development.. Liver fibrosis (5 weeks) and cirrhosis, without (8 weeks) and with ascites (12 weeks), were induced by CCl. In cirrhosis with ascites, MR mRNA and protein expressions were reduced in hepatocytes of hypoxic areas. While in normoxic areas MRs were mainly cytosolic, the remaining MRs in hypoxic areas were mainly localized in the nuclei, indicating activation followed by translocation and degradation. Accordingly, eplerenone treatment prevented nuclear MR translocation and the worsening of cirrhosis. Exposing hepatocytes ex vivo to hypoxia induced nuclear MR translocation and enhanced transcriptional MR activity at response elements of the NF-κB pathway.. We showed for the first time that hypoxia leads to a pathogenetic ligand-independent activation of hepatic MRs during cirrhosis resulting in their nuclear translocation and transcriptional activation of the NF-κB pathway. Treatment with eplerenone prevented the worsening of cirrhosis by blocking this ligand-independent activation of the MR.

Topics: Animals; Carbon Tetrachloride; Cell Hypoxia; Cell Line, Tumor; Eplerenone; HEK293 Cells; Hepatocytes; Humans; Liver; Liver Cirrhosis; Male; Mineralocorticoid Receptor Antagonists; Rats, Wistar; Receptors, Mineralocorticoid; RNA, Messenger

Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH.. To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH.. C57bl6 mice were fed a choline-deficient and amino acid-defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed.. CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2.. The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted.

Topics: Animals; Biomarkers; Disease Models, Animal; Eplerenone; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Receptors, Mineralocorticoid; Spironolactone

The aim of this study was to examine the effects of eplerenone on hepatic fibrosis induced by bile duct ligation (BDL) in rat. Low- (1.0 mg/kg body weight, BW) and high- (4.0 mg/kg BW) dose eplerenone was administered orally for 21 days immediately following BDL. Fibrosis was assessed by measuring the fibrotic area after Sirius red staining. Immunostaining for alpha-smooth muscle actin (SMA), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also carried out. Gene expression levels of procollagen-I, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in the liver were examined by real-time reverse transcriptase polymerase chain reaction. Plasma angiotensin II (ATII) concentration was measured via radioimmunoassay. The area of hepatic fibrosis and alpha-SMA positivity in the high-dose group was significantly decreased compared with that in the BDL group, but not in the low-dose group. 8-OHdG-positive cells in the low- and high-dose groups were significantly decreased compared with those in the BDL group. Immunostaining of 4-HNE in the high-dose group was significantly lower compared with that in the BDL group. Furthermore, TIMP-1 mRNA levels in the low- and high-dose groups were lower than that in the BDL group. The expression of TGF-beta1, CTGF, procollagen-1 and MMP-13 showed no differences. Plasma ATII concentration in the high-dose group was significantly decreased. Eplerenone attenuated the development of BDL-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells and decreasing plasma ATII levels. Eplerenone may prove useful as an alternative treatment for antifibrosis therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Bile Ducts; Deoxyguanosine; Eplerenone; Gene Expression Regulation; Hydroxyproline; Immunohistochemistry; Ligation; Lipid Peroxidation; Liver Cirrhosis; Male; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger; Spironolactone

Topics: Ascites; Eplerenone; Gynecomastia; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Spironolactone