Medications for alcohol use disorder promote abstinence in alcohol-associated cirrhosis: Results from a systematic review and meta-analysis.

BACKGROUND AND AIMS: The role of medications for alcohol use disorder (MAUD) in patients with cirrhosis is not well established. Evidence on the efficacy and safety of these drugs in these patients is scarce. APPROACH AND RESULTS: We performed a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol guidelines on the efficacy of MAUD in patients with cirrhosis. A search was conducted in PubMed, Embase, and Scopus, including all studies until May 2022. The population was defined as patients with AUD and cirrhosis. The primary outcome was alcohol abstinence. Safety was a secondary outcome. We performed a random-effect analysis and expressed the results as relative risk of alcohol consumption. Heterogeneity was measured by I2 . Out of 4095 unique references, 8 studies on 4 different AUD treatments [baclofen (n = 6), metadoxine (n = 1), acamprosate (n = 1), and fecal microbiota transplant (n = 1)] in a total of 794 patients were included. Four were cohort studies, and 4 were RCTs. Only RCTs were included in the meta-analysis. MAUD was associated with a reduced rate of alcohol consumption [relative risk = 0.68 (CI: 0.48-0.97), P = 0.03], increasing alcohol abstinence by 32% compared to placebo or standard treatment, despite high heterogeneity ( I2 = 67%). Regarding safety, out of 165 serious adverse events in patients treated with MAUD, only 5 (3%) were possibly or probably related to study medications. CONCLUSION: MAUD in patients with cirrhosis is effective in promoting alcohol abstinence and has a good safety profile. Larger studies on the effects of MAUD are needed, especially in patients with advanced liver disease.

[Value of autocrine motility factors in the prediction of the disease progression of PBC- associated hepatocellular carcinoma].

Objective: To clarify the value of autocrine motility factor (ATX) in predicting the disease progression of primary biliary cholangitis (PBC)-associated hepatocellular carcinoma (HCC). Methods: A prospective cohort of 179 newly diagnosed autoimmune liver disease (PBC) patients admitted to the Department of Hepatology at the Fifth Medical Center of the People's Liberation Army General Hospital from January 2016 to January 2018 was selected. All PBC patients received ursodeoxycholic acid (UDCA) treatment and were followed up.The endpoint of the follow-up was the occurrence of primary liver cancer. The relationship between ATX and the clinical characteristics of patients and its significance in predicting disease progression and HCC were analyzed. Results: The peripheral blood ATX level was significantly higher in PBC patients than that of alcoholic cirrhosis (t = 3.278, P = 0.001) and healthy controls (t = 6.594, P < 0.001), but there was no significant difference in ATX levels compared with patients with non-PBC- associated HCC (t = -0.240, P = 0.811). The expression of ATX in liver tissue of PBC patients was significantly higher than that of healthy individuals (Z = -3.633, P < 0.001) and patients with alcoholic cirrhosis (Z = -3.283, P < 0.001), while the expression of ATX in the advanced stage was significantly higher than that in early-stage PBC patients (Z = -2.018, P = 0.034). There was a significant difference in baseline ATX levels between PBC patients without HCC and PBC patients with HCC (228.451 ± 124.093 ng/ml vs. 301.583 ± 100.512 ng/ml, t = 2.339, P = 0.021). Multivariate logistic regression analysis showed that ATX was an independent predictor of PBC progression to HCC (OR = 1.245, 95%CI 1.097-1.413). The baseline peripheral blood ATX level in predicting AUROC of PBC-associated HCC was 0.714, 95%CI 0.597-0.857 and the sensitivity and specificity were 84.6%, and 59.0%, respectively. The optimal cutoff value for predicting serum ATX levels in the occurrence of HCC was 235.254 ng/ml. Conclusion: Patients with PBC have significantly higher levels of ATX expression in their peripheral blood and liver tissue, which can be utilized to assess treatment effectiveness and predict disease progression.

Production of Bioactive Substances to Alleviates Hangover and Ethanol-Induced Liver Damage through Fermentation of Oenanthe javanica Using Lactiplantibacillus plantarum.

The purpose of this study is to evaluate the effect of the bioconversion products of Oenanthe javanica extract fermented by Lactiplantibacillus plantarum (OEFL) on relieving hangovers and improving liver function. In addition, the bioactive substance of the OEFL, which alleviates hangover and ethanol-induced liver damage, was identified and its bioactive property was verified through in vivo experiments. In major substances analysis using high-performance liquid chromatography, OEFL produced 9.5-fold higher p-coumaric acid than the O. Javanica extract (OE). In addition, considering that quinic acid, which is not present in the OE, was produced in the OEFL it was confirmed that chlorogenic acid was decomposed into quinic acid by bioconversion. In the in vivo experiment using Sprague-Dawley rats, the OEFL and p-coumaric acid diets reduced blood ethanol, acetaldehyde, GPT, and ALP concentrations, increasing blood albumin concentrations compared to ethanol-administered groups, demonstrating that OEFL and p-coumaric acid, the main substance in the OEFL, improved ethanol-induced liver damage. Furthermore, the OEFL and its main bioactive substance, p-coumaric acid, alleviated liver fibrosis by downregulating TGF-ß, SMAD-2, SMAD-4, α-SMA, and upregulating MMP-1. Therefore, OEFL is expected to be used as a functional food or pharmaceutical material as it has been confirmed to effectively relieve hangovers, prevent liver damage, and delay liver fibrosis in ethanol-induced liver damages.

[Four cases of alcoholic liver cirrhosis in alcohol-dependent patients treated with nalmefene].

Traditionally, abstinence has been regarded as the only appropriate goal in the treatment of alcohol dependence in Japan. Recently, harm reduction by reducing alcohol consumption, which has been used as a treatment approach in Europe, has gained recognition in Japan. The 2018 guideline for the treatment of alcohol dependence in Japan recommends abstinence as the primary goal, but reduction of alcohol consumption is described as an appropriate treatment goal in some patients. Nalmefene is an opioid modulator that is used to reduce alcohol consumption in patients with alcohol dependence. Here, we report the clinical course of alcoholic liver cirrhosis in alcohol-dependent patients who were treated with nalmefene for three months. Their alcohol consumption was reduced, which led to an improvement in liver function. Nalmefene provides a clinical benefit, constitutes a potential pharmacological treatment paradigm in terms of the treatment goal and dosing regimen, and addresses an unmet medical need in patients with alcohol dependence who need to reduce their alcohol consumption.

Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis, and Inflammation in Mice.

Kupffer cell and macrophage (MØ) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells, and expression of C-C chemokine receptor type 2 (Ccr2) and C-C chemokine receptor type 5 (Ccr5) in the livers of patients with ALD, and increased circulating chemokines, C-C chemokine ligand types 2 (CCL2), and C-C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as "prevention" throughout the alcohol feeding or as "treatment" started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen-1) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol-related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and CCL2. CVC administration regimens prevented the increase in infiltrating MØ (F4/80lo CD11bhi ) and reduced proinflammatory Ly6Chi MØ in livers of alcohol-fed mice. CVC increased liver T-cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T-cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte fatty acid synthase (Fasn) and adipose differentiation-related protein (Adrp), whereas it augmented acyl-coenzyme A oxidase 1 (Acox-1), proliferator-activated receptor gamma co-activator alpha (Pgc1α) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide-induced liver injury (TNF-α, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP-ribose polymerase [PARP] and caspase-3 [CASP-3] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. Conclusion: Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.

[Effect of lamivudine and silymarin on liver fibrosis-relevant factors in HBV transgenic mice with alcohol drinking].

OBJECTIVE: To observe the role of lamividine and silymarin preventing and curing liver fibrosis-relevant factors induced by alcohol drinking in hepatitis B virus (HBV) transgenic mice (Tg mice).
 Methods: Forty HBV-Tg BALB/C mice with 1.3 copy were randomly divided into 4 groups: a control group, a model group, a lamivudine group and a silymarin group. Tg mice in control group were treated with normal saline via intragastric administration; Tg-mice in the model group were treated with 50% alcohol (5 mL/kg) once a day via intragastric administration; while Tg-mice in lamivudine group and silymarin group were treated with alcohol (5 mL/kg) plus laminvudine (100 mg/kg) and silymarin (200 mg/kg) once a day via intragastric administration respectively. All groups were raised for 10 weeks. The levels of HBV-DNA copy number, ALT, AST in serum, the degree of inflammation, the degree of fibrosis, the mRNA expression levels of TGF-ß1, Smad3, Smad7 and connective tissue growth factor (CTGF), and the protein expression levels of TGF-ß1, CTGF and α-SMA in liver tissue were detected. All the images were scanned with electronic computer and the data were analyzed with SPSS13.0 software.
 Results: Compared with the control group, liver injury were significantly aggravated, while HBV-DNA copies, mRNA levels of TGF-ß1, Smad3, Smad7 and CTGF as well as the protein levels of TGF-ß1, CTGF and α-SMA were significantly increased (P<0.05). Compared with the model group, liver injury were significantly attenuated in silymarine group and lamivudine group, while mRNA levels of TGF-ß1, Smad3 and CTGF as well as the protein levels of TGF-ß1, CTGF and α-SMA were significantly decreased; mRNA level of Smad7 was further increased (P<0.05); the levels of ALT and AST in serum were decreased in the silymarine group (P<0.05).
 Conclusion: Lamivudine and silymarin relieve the histological damage in the liver of alcohol-fed Tg mice. The mechanisms for the beneficial effects of lamivudine or silymarin might be related to inhibiting the expression of TGF-ß1, Smad3 and CTGF, modulating the expression of Smads and suppressing the activation of HSC.

NEW HEPATIC AND NEUROLOGICAL CLINICAL IMPLICATIONS OF LONG-CHAIN PLANT POLYPRENOLS ACTING ON THE MAMMALIAN ISOPRENOID PATHWAY.

The mammalian isoprenoid synthesis pathway (also known as the mevalonate pathway) is fundamental to the metabolism and health of organisms, with products such as cholesterol (sterol isoprenoid), ubiquinone (coenzyme Q) and dolichol (non-sterol isoprenoids) having great importance to mammalian biology and physiology. Targeting the isoprenoid pathway results in novel therapeutic options for a diverse range of conditions. Plant polyprenols are biologically active molecules that affect the isoprenoid pathway - toxic side effects have never been observed during treatment with our pharmaceuti- cal-grade polyprenols (Ropren*). Statins and bisphosphonates also act on this pathway but have the disadvantage of causing numerous side effects. Our unique ability to produce Ropren' containing not less than 95% pure polyprenols has enabled their clinical use in Russia for around eight years and has also enabled researchers to conduct trials into other therapeutic uses. Although polyprenols can treat conditions such as viral, bacterial and fungal infections, inflammation and other immune conditions, this paper focuses on the new pre-clinical and clinical effects of polyprenols in hepatic and neurological conditions. Recent pre-clinical studies have shown treatment with polyprenols from conifers had a range of neurological and cognitive effects, including improved cognitive performance in a rat model relevant to Alzheimer's disease and healthy levels of myelination in mice with an experimental model of multiple sclerosis. Early clinical data has shown Ropren' treatment improved antioxidant levels in people with diabetes and improved liver function in patients on chemotherapy treatment. Ropren' also had positive effects on electroencephalograms of people with alcohol-induced cirrhosis and Alzheimer's disease and significantly decreased symptoms in people with depression. These results pave the way for larger clinical trials and show how Ropren' is a valuable clinical tool to treat a wide range of liver and neurological conditions.

Diethylcarbamazine: possible therapeutic alternative in the treatment of alcoholic liver disease in C57BL/6 mice.

Alcoholic liver disease is a major cause of chronic liver disease worldwide. Diethylcarbamazine (DEC) is a drug that has anti-inflammatory properties due to its effects on the metabolism of arachidonic acid. The present study examined the anti-inflammatory effects of DEC on the mechanisms of alcoholic liver disease. C57BL/6 mice were divided into seven groups: (i) control; (ii) DEC 50 mg/kg; (iii) alcohol; (iv) alcohol + DEC 50 mg/kg; (v) alcohol + celecoxib 50 mg/kg; (vi) alcohol + pyrrolidine dithiocarbamate 100 mg/kg; and (vii) alcohol + pyrrolidine dithiocarbamate 100 mg/kg + DEC 50 mg/kg. Liver fragments were stained with haemotoxylin-eosin and Sirius red, and processed for immunofluorescence, western blot, and immunohistochemistry. Serum was also collected for biochemical measurements. Alcohol induced liver damage, elevated collagen content, and increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and inflammatory markers (tumour necrosis factor-α, interferon-γ, interleukin-1ß, inducible nitric oxide synthase, cyclooxygenases-2, and transforming growth factor-ß). Treatment with DEC was able to reduce liver damage, collagen content, the expression of nuclear factor kappa-light-chain-enhancer of activated B cells and inflammatory markers; it also ameliorated biochemistry parameters (total cholesterol, high-density lipoprotein cholesterol, triglyceride content and aspartate aminotransferase) and increased the expression of anti-inflammatory markers (p-5' adenosine monophosphate-activated protein kinase and interleukin-10). Future clinical trials may demonstrate that oral administration of DEC may be suitable for the treatment of alcoholic liver disease and other liver diseases.

Inhibition of mammalian target of rapamycin aggravates the respiratory burst defect of neutrophils from decompensated patients with cirrhosis.

UNLABELLED: Cirrhosis is commonly accompanied by impaired defense functions of polymorphonuclear leucocytes (PMNs), increased patient susceptibility to infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity is dependent on a massive production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), termed respiratory burst (RB). Rapamycin, an antagonist of mammalian target of rapamycin (mTOR), may be used in the treatment of HCC and in transplanted patients. However, the effect of mTOR inhibition on the PMN RB of patients with cirrhosis remains unexplored and was studied here using the bacterial peptide, formyl-Met-Leu-Phe (fMLP), as an RB inducer. fMLP-induced RB of PMN from patients with decompensated alcoholic cirrhosis was strongly impaired (30%-35% of control) as a result of intracellular signaling alterations. Blocking mTOR activation (phospho-S2448-mTOR) with rapamycin further aggravated the RB defect. Rapamycin also inhibited the RB of healthy PMNs, which was associated with impaired phosphorylation of the NOX2 component, p47phox (phox: phagocyte oxidase), on its mitogen-activated protein kinase (MAPK) site (S345) as well as a preferential inhibition of p38-MAPK relative to p44/42-MAPK. However, rapamycin did not alter the fMLP-induced membrane association of p47phox and p38-MAPK in patients' PMNs, but did prevent their phosphorylation at the membranes. The mTOR contribution to fMLP-induced RB, phosphorylation of p47phox and p38-MAPK was further confirmed by mTOR knockdown in HL-60 cells. Finally, rapamycin impaired PMN bactericidal activity, but not bacterial uptake. CONCLUSION: mTOR significantly up-regulates the PMN RB of patients with cirrhosis by p38-MAPK activation. Consequently, mTOR inhibition by rapamycin dramatically aggravates their PMN RB defect, which may increase patients' susceptibility to infection. Thus, concerns should be raised about the use of rapamycin in immuno-depressed patients.

Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: a mechanistic approach.

Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4g/kg b.wt for 90days. After 90days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250mg/kg b.wt) and AA (250mg/kg b.wt) supplemented groups and maintained for 30days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKß and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-ß1 and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α1 (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKß, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis.

Utilization of baclofen in maintenance of alcohol abstinence in patients with alcohol dependence and alcoholic hepatitis with or without cirrhosis.

AIM: To report the efficacy and safety of baclofen in improving clinical state in patients with alcoholic hepatitis. METHOD: Single center, open, retrospective study analyzing the effects of baclofen utilized over 12 months in patients with alcoholic hepatitis with or without cirrhosis and alcohol dependence on these liver parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (Tbili), prothrombin time (PT), international normalized ratio (INR), albumin and Model for End-Stage Liver Disease (MELD) score. RESULTS: Out of 40 patients, 35 were treated with baclofen. On average, baclofen was used for 5.8 months. A significant decrease in the mean AST, ALT, Tbili, INR, PT and MELD score was seen when comparing pre-baclofen use compared with post-baclofen use. Of the 35 patients who were started on baclofen, 34 (97%) remained abstinent. There were no serious adverse events. CONCLUSIONS: Baclofen's safety and efficacy in improving the clinical condition patients with alcoholic liver disease has been supported. Randomized prospective studies with longer duration of baclofen in this population may further optimize its use and corroborate efficacy.

[A NEW APPROACH TO TREATMENT LIVER CIRRHOSIS IN CONNECTION WITH INTESTINAL DYSBIOSIS].

In order to increase the effectiveness of treatment of the liver cirrhosis were examined 65 patients, we studied the effect on the features flow of intestine microbiocenosis and were are included to the combined treatment the synbiotic medications "Bifilakt extra". Inclusion to the combined treatment of the examined patients with liver cirrhosis synbiotic medications "Bifilakt extra" probably led to better reduction of subjective and objective signs of cirrhosis and intensity of functional biochemical syndromes, symptoms of hepatic encephalopathy.

Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis.

BACKGROUND AND AIM: Cirrhotic patients are predisposed to intestinal bacterial overgrowth with translocation of bacterial products which may deteriorate liver hemodynamics. Having shown that short-term administration of rifaximin improves liver hemodynamics in decompensated cirrhosis, we conducted this study to investigate the effect of intestinal decontamination with rifaximin on the long-term prognosis of patients with alcohol-related decompensated cirrhosis (Child-Pugh > 7) and ascites. METHODS: Patients who had received rifaximin and showed improved liver hemodynamics were enrolled in the current study and continued to receive rifaximin (1200 mg/day). Each patient was matched by age, sex, and Child-Pugh grade to two controls and followed up for up to 5 years, death or liver transplantation. Survival and risk of developing portal hypertension-related complications were compared between rifaximin group and controls. RESULTS: Twenty three patients fulfilled the inclusion criteria and matched with 46 controls. Patients who received rifaximin had a significant lower risk of developing variceal bleeding (35% vs. 59.5%, P = 0.011), hepatic encephalopathy (31.5% vs. 47%, P = 0.034), spontaneous bacterial peritonitis (4.5% vs. 46%, P = 0.027), and hepatorenal syndrome (4.5% vs. 51%, P = 0.037) than controls. Five-year cumulative probability of survival was significantly higher in patients receiving rifaximin than in controls (61% vs. 13.5%, P = 0.012). In the multivariate analysis, rifaximin administration was independently associated with lower risk of developing variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and higher survival. CONCLUSIONS: In patients with alcohol-related decompensated cirrhosis, long-term rifaximin administration is associated with reduced risk of developing complications of portal hypertension and improved survival.

A case of drug-induced myopathy in alcoholic cirrhosis caused by voriconazole.

BACKGROUND: Voriconazole is a new generation of broad-spectrum antifungal agents commonly used in the treatment of invasive aspergillus infections. CASE REPORT: We reported a rare case of myopathy induced by voriconazole, which showed severe muscle pain and significantly elevated myocardial enzymes. Enzymes eventually achieved good efficacy by switching voriconazole to micafungin and the use of L-carnitine. CONCLUSIONS: This reminded us it was necessary to be vigilant for rare adverse reactions of voriconazole in the population with liver dysfunction, the elderly population, and people with multiple underlying diseases in clinical practice. During medication of voriconazole, close attention should be paid to the occurrence of adverse reactions to avoid life-threatening complications.

Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites.

Circulating levels of endotoxin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α increase with intestinal bacterial overgrowth and translocation, and are believed to be involved in the pathogenesis of hyperdynamic circulatory syndrome and functional renal failure in patients with advanced cirrhosis. We investigated the effects of the antibiotic rifaximin on systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. We measured mean arterial pressure, cardiac output (CO) by Doppler ultrasound, systemic vascular resistance (as the ratio of mean arterial pressure:CO), plasma renin activity, levels of plasma aldosterone, the glomerular filtration rate by plasma clearance of technetium-99m-DTPA, natriuresis, levels of plasma endotoxin, and serum levels of IL-6 and TNF-α in 13 patients at baseline and after 4 weeks of treatment with rifaximin. Rifaximin treatment significantly reduced CO and significantly increased systemic vascular resistance, in association with a significant decrease in plasma rennin activity. The therapy also significantly increased the glomerular filtration rate and natriuresis while reducing levels of endotoxin, IL-6, and TNF-α. Intestinal decontamination with rifaximin improved systemic hemodynamics and renal function in patients with advanced cirrhosis.

Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study.

BACKGROUND: Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo. However, no study was done in humans with alcoholic liver disease. AIM: To investigate the antifibrotic effect of angiotensin II type 1 receptor (AT1-R) blocking agents (ARB) in patients with alcoholic liver disease. METHODS: The primary outcome was improvement in patients' histological features. Eighty-five patients with compensated alcoholic liver fibrosis (≥ F2) which was confirmed by baseline liver biopsy were randomized (intention-to-treat (ITT)) to receive either ARB, candesartan (8 mg/day) with ursodeoxycholic acid (UDCA) (600 mg/day) (n = 42) or UDCA alone (n = 43) as control for 6 months and follow-up liver biopsies were conducted. RESULTS: According to the Laennec fibrosis system, candesartan showed significantly higher rates of histological improvements (ITT, 33.3% vs. 11.6%, P = 0.020). In addition, the fibrosis score was significantly reduced from 3.4 ± 1.4 to 3.1 ± 1.5 (P = 0.005) in the candesartan group. Candesartan also reduced the area of fibrosis and α-smooth muscle actin positive from 11.3 ± 6.0 to 8.3 ± 4.7 and 28.7 ± 10.5 to 23.9 ± 10.3 (%), and the hydroxyproline levels (µg/g liver tissue) from 7.8 ± 2.4 to 6.3 ± 1.7 respectively (P < 0.05). In addition, the relative expression of transforming growth factor-ß1(TGF-ß1), collagen-1, AT1-R, tissue inhibitor of metalloproteinase 1 (TIMP-1), metalloproteinases2 (MMP2), Rac1 and p22phox by real-time RT-PCR decreased in the candesartan group (P < 0.05). Mean arterial blood pressure in the candesartan group decreased mildly but significantly (P < 0.001). No significant complications and side effects were observed during the present study. CONCLUSIONS: Administration of ARB in compensated alcoholic liver disease induces improvement of fibrosis in histological and quantitative measurements.

The role of glucocorticoids in sodium retention in cirrhotic patients: a double blind, randomized, crossover study.

OBJECTIVE: Cirrhotic patients have an increased ratio of urinary cortisol to cortisone metabolites, indicating decreased renal 11-ß-hydroxysteroid dehydrogenase type-2 activity. This suggests that cortisol--by activation of the mineralocorticoid receptor--may contribute to the abnormal sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. METHODS: A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout interval of 14 days separated the two periods. After a basal period of 36 h, dexamethasone (0.5 mg every 6 h) or placebo was given for two days. Urine was collected for 12 h periods, and the concentrations of sodium, potassium, creatinine, cortisol and cortisol metabolites were determined. Blood samples for hemoglobin, glucose, sodium, potassium, creatinine, aldosterone and cortisol were obtained daily. RESULTS: Dexamethasone treatment decreased S-cortisol 92.3% (82.9-93.4%) (median and range) compared with that in the basal period. Natriuresis (dexamethasone--placebo) increased 55.1 (-26.4-168.7) mmol/day (median and range). No statistically significant differences (dexamethasone--placebo) were found in changes in body weight (0.00 (-0.45-2.20) kg/day), diuresis (0.56 (-0.35-1.43) L/day) or mean arterial pressure (8.33 (-16.0-41.3) mmHg) (median and range) in reference to the preceding 24 h basal period. CONCLUSION: These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver.

Argatroban dose reductions for suspected heparin-induced thrombocytopenia complicated by child-pugh class C liver disease.

OBJECTIVE: To report our experience of reduced-dose argatroban in a patient with suspected heparin-induced thrombocytopenia (HIT) and Child-Pugh class C liver disease and review the relevant literature to summarize current recommendations on argatroban use in patients with severe liver disease. CASE SUMMARY: A 58-year-old male with Child-Pugh class C liver disease (Model for End-Stage Liver Disease [MELD] score = 31, total bilirubin 4.5 mg/dL) and hemodialysis-dependent renal failure was hospitalized with acute deep vein thrombosis (DVT). Three days after heparin initiation for DVT, he developed thrombocytopenia. Given his heparin exposure (both for treatment of DVT and ongoing hemodialysis), HIT was suspected and all heparinoids were immediately discontinued. Argatroban was initiated for the treatment of HIT while laboratory testing for HIT antibodies and the serotonin release assay were completed. Because of the patient's advanced liver disease, the starting dose of argatroban was reduced to 0.2 µg/kg/min, with frequent monitoring of the activated partial thromboplastin time (aPTT) (goal 60-85 seconds). Despite this dose reduction, the aPTT was supratherapeutic. Following further dose reductions, a final argatroban maintenance dose of 0.05 µg/kg/min was necessary for the attainment of goal aPTTs. DISCUSSION: Reducing the starting dose of argatroban to 0.5 µg/kg/min is recommended in patients with liver disease. Nevertheless, this recommended dose is largely based on data from patients with more moderate liver disease (eg, Child-Pugh class A or B), and dosing in more advanced liver disease remains largely unexplored. Patients with more advanced liver disease may require additional dose reductions to avoid supratherapeutic concentrations of anticoagulation agents and to minimize bleeding risk. CONCLUSIONS: This report illustrates the importance of careful selection of argatroban dosing and appropriate aPTT monitoring in patients with severe liver disease. Excessive anticoagulation may precipitate major bleeding complications, placing patients with this complicated disease at undue risk.

Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis.

PURPOSE: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. METHODS: The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. RESULTS: Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. CONCLUSION: In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.