losartan-potassium and Liver-Cirrhosis

Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival.. To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease.. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type.. We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language.. We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I. We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I. G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.

Topics: Acute-On-Chronic Liver Failure; Adult; Erythropoietin; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Granulocyte Colony-Stimulating Factor; Growth Hormone; Humans; Intercellular Signaling Peptides and Proteins; Liver Cirrhosis; Quality of Life; Stem Cells

The main function of erythropoietin (EPO) is to maintain red blood cell mass, but in recent years, increasing evidence has suggested a wider biological role not solely related to erythropoiesis, e.g. angiogenesis and tissue protection. EPO is produced in the liver during fetal life, but the main production shifts to the kidney after birth. The liver maintains a production capacity of up to 10% of the total EPO synthesis in healthy controls, but can be up-regulated to 90-100%. However, the hepatic EPO synthesis has been shown not to be adequate for correction of anemia in the absence of renal-derived EPO. Elevated circulating EPO has been reported in a number of diseases, but data from cirrhotic patients are sparse and the level of plasma EPO in patients with cirrhosis is controversial. Cirrhosis is characterized by liver fibrosis, hepatic dysfunction and the release of proinflammatory cytokines, which lead to arterial hypotension, hepatic nephropathy and anemia. An increase in EPO due to renal hypoperfusion, hypoxia and anemia or an EPO-mediated hepato-protective and regenerative mechanism is plausible. However, poor hepatic synthesis capacity, a decreasing co-factor level and inflammatory feedback mechanisms may explain a potential insufficient EPO response in end-stage cirrhosis. Finally, the question remains as to whether a potential increase in EPO production in certain stages of cirrhosis originates from the kidney or liver. This paper aims to review contemporary aspects of EPO relating to chronic liver disease.

Topics: Animals; Endothelins; Erythropoietin; Hemodynamics; Homeostasis; Humans; Liver; Liver Cirrhosis; Neovascularization, Physiologic; Nitric Oxide

Currently available anti-HCV therapy is effective in only half of the patients and limited by side effects that often necessitate discontinuation. Therefore, new treatment strategies are being developed including (i) the optimization of current regimens, (ii) the use of additional agents working via novel mechanisms, and (iii) anti-fibrotic strategies. Many new antiviral compounds are now being studied in preclinical and clinical trials. This review will focus on drugs that have already entered the stage of phase 2 or phase 3 studies.

Topics: Antidepressive Agents; Antiviral Agents; Clinical Trials as Topic; Erythropoietin; Genome, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Liver Cirrhosis; Protease Inhibitors; Purine-Nucleoside Phosphorylase; Pyrimidine Nucleosides; Ribavirin; Viral Hepatitis Vaccines

Exogenous growth factor-mobilized bone marrow (BM) stem cells have shown a differential response in the management of decompensated cirrhosis (DC). This study was designed to evaluate potential clinical benefit of adding Erythropoietin (EPO) in granulocyte-colony stimulating factor (G-CSF)-mobilized stem cell therapy, possible mechanisms of regeneration and predictive factors of regenerative response.. Sixty consecutive DC patients received either G-CSF with EPO (Group A; n = 30) or G-CSF and placebo (Group B; n = 30) for 2 months and were carefully followed up for 1 year. Baseline and post-treatment liver biopsy, BM biopsy and BM aspirate were analysed for fibro-inflammatory and regenerative response and BM hematopoietic reservoir.. Addition of EPO to G-CSF showed a significant improvement in Child-Pugh score (P = 0.03) and MELD score (P = 0.003) as compared to G-CSF alone, with reduction in mortality (16.6% vs 36.7%, P = 0.09). The combination arm also demonstrated a decreased incidence of acute kidney injury (P < 0.001), encephalopathy (P = 0.005) and refilling of ascites (P = 0.03). Compared to monotherapy, it increased CD163+ macrophages (P = 0.013), Ki67+ index (P < 0.001) with decrease in α-SMA levels (P < 0.001) in liver tissue. The response was better with grade 1 and 2 than with grade 3 ascites; Child B cirrhosis and MELD < 16. Non-responders had lower hematopoietic stem cells (HSCs) at baseline. On multivariate analysis, the liver disease severity (MELD < 16) and a relatively preserved BM (BM-HSCs > 0.4) predicted therapeutic response (AUROC = 0.82).. Early DC (MELD < 16) patients with mild-moderate ascites and those with a healthy cellular baseline BM respond better to growth factor therapy. Addition of EPO to G-CSF provides better regenerative response than G-CSF monotherapy.

Topics: Adult; Combined Modality Therapy; Double-Blind Method; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; India; Liver; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Multivariate Analysis; Severity of Illness Index; Stem Cell Niche; Treatment Outcome

Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis.. In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 μg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months.. Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group.. In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.

Topics: Adult; Biopsy; Darbepoetin alfa; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; India; Injections, Subcutaneous; Kaplan-Meier Estimate; Liver; Liver Cirrhosis; Liver Regeneration; Male; Middle Aged; Paracentesis; Proportional Hazards Models; Prospective Studies; Risk Factors; Severity of Illness Index; Shock, Septic; Time Factors; Treatment Outcome

To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A.. A non-randomised, multicentre, single-dose, open-label study in patients with HI (n=12) and healthy subjects (n=12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 mug), and were then followed for approximately 8 weeks. The area under the concentration-time curve (AUC) from drug administration to last measurable concentration (AUC(last)), and maximum C.E.R.A. concentration (C(max)) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUE(corr)) for reticulocyte count was the primary PD parameter.. The PK profile was similar in patients and healthy subjects (AUC(last): 6678 vs 6985 ng*h/mL; C(max): 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7-9 days post-dose and returning to baseline by Day 22. Although mean AUE(corr) was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects.. Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.

Topics: Adolescent; Adult; Aged; Erythropoiesis; Erythropoietin; Female; Hematinics; Humans; Liver Cirrhosis; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Reticulocytes

Recurrence of hepatitis C virus (HCV) infection is a relevant problem of liver transplantation programs. We evaluated the effect of antiviral therapy on disease progression in 81 HCV-infected liver transplantation recipients.. Patients with mild hepatitis C recurrence (fibrosis stage F0 to F2, n = 54) were randomized to no treatment (group A, n = 27) or peginterferon alfa-2b/ribavirin for 48 weeks (group B, n = 27). Patients with severe recurrence (F3 to F4, cholestatic hepatitis) were treated (group C, n = 27). All patients (n = 81) underwent a liver biopsy at baseline and after follow-up; paired hepatic venous pressure gradient (HVPG) measurements were available in 51 patients.. Thirteen (48%) patients of group B and 5 (18.5%) of group C achieved sustained virological response. Liver fibrosis progressed > or =1 stage in 40 (49%) of 81 patients: 19 (70%) of group A versus 7 (26%) of group B (P = .001) and in 14 (54%) of group C. HVPG increased (6.5 to 13 mm Hg, P < .01) in patients in whom fibrosis worsened, whereas it decreased (5 to 3.5 mm Hg, P = .017) or remained unchanged in those with fibrosis improvement or stabilization, respectively. The only variable independently associated with fibrosis improvement/stabilization was treatment (odds ratio [OR] =3.7, 95% confidence interval [CI] 1.3 to 10, P = .009). Among treated patients, alanine aminotransferase (ALT) normalization and viral clearance were independently associated with histological or hemodynamic improvement/stabilization (OR 5.3, 95% CI 1.5 to 18, P < .01; OR 7.4, 95% CI 1.4 to 38, P = .01; respectively).. Our data demonstrate that in liver transplantation recipients, antiviral therapy slows disease progression (particularly in sustained virological responders), as shown by its effects on liver histology and on HVPG.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Biopsy; Darbepoetin alfa; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Portal Pressure; Recombinant Proteins; Ribavirin; Secondary Prevention

Anemia and decreased health-related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb < or = 12 g/dL) HCV-infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8-week double-blind phase (DBP), followed by an 8-week open-label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV-infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion, epoetin alfa provided clinically significant HRQL improvement in HCV-infected patients receiving IFN/RBV therapy.

Topics: Adult; Aged; Anemia; Antiviral Agents; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Hepatitis C, Chronic; Humans; Interferon-alpha; Liver Cirrhosis; Male; Middle Aged; Quality of Life; Recombinant Proteins; Ribavirin

We evaluated the benefit of autologous blood transfusion and the effect of recombinant human erythropoietin (rh-EPO) on preoperative autologous blood donation for hepatectomy in patients with cirrhosis.. Forty-two patients with cirrhosis and hepatocellular carcinoma underwent hepatectomy, 21 of whom (group A) donated autologous blood before operation. Eleven of these patients (group A1) were administered rh-EPO before operation, and ten patients (group A2) were untreated. Twenty-one patients (group B) did not donate autologous blood.. The frequency of homologous blood transfusion was 24% in group A and 62% in group B (p < 0.05). Preoperative erythropoiesis increased markedly in group A1, and postoperative erythropoietin production was not suppressed in this group. Postoperative hematocrits recovered significantly more rapidly in patients transfused with only autologous blood. Postoperative serum total bilirubin concentrations were significantly higher in patients with transfused homologous blood.. Autologous blood transfusion yields clinically superior results for hepatectomy in patients with cirrhosis when compared with homologous transfusion. Preoperative rh-EPO administration minimizes presurgical decreases in hematocrit caused by autologous blood donation.

Topics: Adult; Aged; Bilirubin; Blood Transfusion, Autologous; Carcinoma, Hepatocellular; Erythropoietin; Female; Hematocrit; Hepatectomy; Humans; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Postoperative Complications; Recombinant Proteins

Topics: Blood Transfusion, Autologous; Erythropoietin; Humans; Liver Cirrhosis; Phosphates; Preoperative Care; Recombinant Proteins

This study aims to determine if metabolic-dysfunction-associated fatty liver disease (MAFLD) or advanced liver fibrosis is associated with erythropoietin stimulating agent (ESA) hypo-responsiveness in hemodialysis patients.. In a cross-sectional study of 379 hemodialysis patients, FibroTouch transient elastography was performed on all patients. Erythropoeitin resistance index (ERI) was used to measure the responsiveness to ESA. Patients in the highest tertile of ERI were considered as having ESA hypo-responsiveness.. The percentage of patients with ESA hypo-responsiveness who had MAFLD was lower than patients without ESA hypo-responsiveness. FIB-4 index was significantly higher in ESA hypo-responsive patients. In multivariate analysis, female gender (aOR = 3.4, 95% CI = 1.9-6.2, p < 0.001), dialysis duration ≥50 months (aOR = 1.8, 95% CI = 1.1-2.9, p < 0.05), elevated waist circumference (aOR = 0.4, 95% CI = 0.2-0.8, p = 0.005), low platelet (aOR = 2.6, 95% CI 1.3-5.1, p < 0.01), elevated total cholesterol (aOR = 0.5, 95% CI 0.3-0.9, p < 0.05) and low serum iron (aOR = 3.8, 95% CI = 2.3-6.5, p < 0.001) were found to be independent factors associated with ESA hypo-responsiveness. Neither MAFLD nor advanced liver fibrosis was independently associated with ESA hypo-responsiveness. However, every 1 kPA increase in LSM increased the chance of ESA-hyporesponsiveness by 13% (aOR = 1.1, 95% CI =  1.0-1.2, p = 0.002) when UAP and LSM were used instead of presence of MAFLD and advanced liver fibrosis, respectively.. MAFLD and advanced liver fibrosis were not independently associated with ESA hypo-responsiveness. Nevertheless, higher FIB-4 score in ESA hypo-responsive group and significant association between LSM and ESA hypo-responsiveness suggest that liver fibrosis may be a potential clinical marker of ESA hypo-responsiveness.

Topics: Anemia; Cross-Sectional Studies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Liver Cirrhosis; Renal Dialysis

Topics: Animals; Erythropoietin; Liver Cirrhosis; Male; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Thioacetamide; Toll-Like Receptor 4

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

Topics: Animals; Carbon Tetrachloride Poisoning; Cation Transport Proteins; Cyclohexylamines; Cytokines; Erythropoiesis; Erythropoietin; Female; Ferroptosis; Hepatocytes; Homeostasis; Iron; Iron Overload; Iron, Dietary; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Phenylenediamines; Transferrin

Mesenchymal stem cell (MSC)-based cell transplantation is an effective means of treating chronic liver injury, fibrosis and end-stage liver disease. However, extensive studies have found that only a small number of transplanted cells migrate to the site of injury or lesion, and repair efficacy is very limited.. Bone marrow-derived MSCs (BM-MSCs) were generated that overexpressed the erythropoietin (EPO) gene using a lentivirus. Cell Counting Kit-8 was used to detect the viability of BM-MSCs after overexpressing EPO. Cell migration and apoptosis were verified using Boyden chamber and flow cytometry, respectively. Finally, the anti-fibrosis efficacy of EPO-MSCs was evaluated in vivo using immunohistochemical analysis.. EPO overexpression promoted cell viability and migration of BM-MSCs without inducing apoptosis, and EPO-MSC treatment significantly alleviated liver fibrosis in a carbon tetrachloride (CCl. EPO-MSCs enhance anti-fibrotic efficacy, with higher cell viability and stronger migration ability compared with treatment with BM-MSCs only. These findings support improving the efficiency of MSCs transplantation as a potential therapeutic strategy for liver fibrosis.

Topics: Animals; Erythropoietin; Fibrosis; Liver Cirrhosis; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability.. This was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child-Pugh score 7-9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function.. In subjects with moderate hepatic impairment, area under the concentration-time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (C max) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1-175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5-104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t ½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (V z/F) and t ½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (E max) were 31 % (GMR 68.95 %; 90 % CI 29.29-162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95-94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated.. This study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Area Under Curve; Erythropoietin; Female; Glycine; Half-Life; Humans; Hypoxia-Inducible Factor 1; Isoquinolines; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors; Young Adult

Topics: Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Liver; Liver Cirrhosis; Male

HCV infection is related to hepatic disease and mixed cryoglobulinaemia (MC). Renal involvement is reported in one third of cryoglobulinaemic patients. The combination of HCV related MC with renal involvement has been associated with poor survival and identified as Hepatitis C Virus Risk Syndrome (HCV RS). Here we describe antiviral treatment and management of side effects (anaemia and neutropenia) with RHuEpo and G CSF in a rare case of HCV RS.

Topics: Anemia; Antiviral Agents; Cryoglobulinemia; Drug Therapy, Combination; Erythropoietin; Glomerulonephritis, Membranoproliferative; Granulocyte Colony-Stimulating Factor; Hepatitis C; Humans; Interferons; Liver Cirrhosis; Male; Middle Aged; Neutropenia; Recombinant Proteins; Ribavirin; Risk Factors; Treatment Outcome

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-α (10 μg/kg i.p.) or physiological saline every third day, beginning 24 h after BDL. Mice were killed at 2, 5, 14, and 28 days after BDL. Beside hematological parameters, markers of inflammation and fibrosis were assessed histomorphometrically and immunohistochemically as well as by quantitative real-time PCR. In addition, a 7-week survival study was performed. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased expression of profibrotic gene transcripts. Darbepoetin-α treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, decreased levels of profibrotic genes, and lowered collagen deposition. Moreover, darbepoetin-α significantly reduced systemic anemia caused by BDL. Finally, darbepoetin-α treatment significantly prolonged the survival time after BDL. This study suggests that darbepoetin-α, which is a clinically well-established substance, might be used as an efficient therapeutic option for patients with chronic cholestatic liver disease.

Topics: Alanine Transaminase; Anemia; Animals; Cholestasis, Extrahepatic; Collagen; Common Bile Duct; Cytophotometry; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Hematinics; Immunohistochemistry; Inflammation; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Necrosis

Although the incidence of (myelodysplastic syndrome (MDS)) is higher among heart and lung transplant recipients than the general population, the same has not been shown in liver transplant (OLT) patients. We present the second known case of MDS after OLT. Case reports of MDS in OLT were identified using PubMed. Patient data were gathered from the patient and the medical record. A 54-year-old Caucasian man underwent OLT in 2003 and again in 2004 for hepatitis C-related cirrhosis. In 2007, the patient developed weakness, malaise, and shortness of breath. Laboratory studies revealed pancytopenia. Bone marrow biopsy showed MDS, with refractory anemia and excess blasts-1. The patient underwent chemotherapy and reduction in immunosuppression without a clinical response. Our experience suggested that MDS, although rare, should be considered in the differential diagnosis of pancytopenia after OLT. Once diagnosed, immunosuppression reduction, chemotherapy, and even stem cell transplantation may be the appropriate treatment in selected candidates.

Topics: Anemia; Antiviral Agents; Erythropoietin; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Myelodysplastic Syndromes; Polyethylene Glycols; Recombinant Proteins; Recurrence; Reoperation

Topics: Biomarkers; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Liver Cirrhosis; Male; Prognosis; Reference Values; Sensitivity and Specificity

We report the efficacy, tolerability and cost of erythocytoapheresis plus recombinant human erythropoietin (rHuEPO) in three patients with severe hereditary hemochromatosis (HH). Results indicate that this regimen could be a valid therapeutic alternative in complicated HH patients. Its cost, however, limits its use to patients whose clinical conditions prevent a proper phlebotomy regimen.

Topics: Adult; Combined Modality Therapy; Cytapheresis; Erythropoietin; Hemochromatosis; Hemochromatosis Protein; Histocompatibility Antigens Class I; Humans; Iron Overload; Liver Cirrhosis; Male; Membrane Proteins; Middle Aged; Recombinant Proteins; Treatment Outcome

Topics: Biomarkers; Erythropoietin; Hepatitis, Chronic; Humans; Liver Cirrhosis

Treatment-induced anemia undermines the efficacy of antiviral therapy in hepatitis C by mandating ribavirin dose reduction and diminishing adherence to therapy. Erythropoietic growth factors (EGFs) may correct treatment-induced anemia, facilitate maintenance of full-dose therapy, and improve rates of sustained virologic response (SVR). We sought to determine the cost effectiveness of adjunctive treatment with an EGF vs standard care in the treatment of hepatitis C.. We used a decision analysis to calculate the cost effectiveness of 2 treatment strategies for a patient cohort with chronic hepatitis C, increased transaminase levels, and no cirrhosis who were receiving pegylated-interferon and ribavirin (RBV): (1) RBV dose-reduction for anemia, followed by discontinuation of therapy if anemia persisted (standard care strategy), (2) adjunctive treatment with EGF therapy for anemia, with RBV dose reduction reserved for persistent anemia despite EGF therapy (EGF strategy). We conducted cost-effectiveness and cost-utility analyses to compare short- and long-term outcomes between the strategies.. The percentage achieving SVR was 52.3% in the standard care strategy and 59.5% in the EGF strategy. Compared with standard care, the EGF strategy cost an incremental $36,568 per unadjusted life-year gained and $16,443 per quality-adjusted life-year gained. In a sensitivity analysis, if a third-party payer was willing to pay $50,000 per quality-adjusted life-year gained for the use of an EGF, then 86.1% of patients would be within the budget.. Compared with standard care, adjunctive therapy with an EGF for the management of treatment-induced anemia may increase the probability of achieving SVR, increase unadjusted lifespan, and increase quality-adjusted lifespan at an acceptable cost.

Topics: Anemia; Antiviral Agents; Cohort Studies; Cost-Benefit Analysis; Darbepoetin alfa; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Transaminases; Treatment Outcome

Current regular blood transfusion programs and chelation treatment have considerably improved survival of patients with thalassemia, which resulted in a larger proportion of adult patients. However, disease- and treatment-related complications in these patients progress over time, causing severe morbidity and shortened life expectancy. Stem cell transplantation still remains the only cure currently available for patients with thalassemia. This study updates transplant outcomes in 107 adult patients with median age of 22 years (range, 17-35 years) who received bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical related donors between 1988 and 1996 (group A) and describes the results of BMT in 15 adult patients with median age of 21 years (range, 17-31 years) who were treated with a new treatment protocol (Protocol 26) between 1997 and 2003 (group B). The probability of survival, event-free survival, nonrejection mortality, and rejection for group A patients were 66%, 62%, 37%, and 4%, respectively, with a median follow-up of 12 years (range, 8.3-16.2 years). Group B patients treated with the new protocol had some improvement in thalassemia-free survival (67%) and lower transplant-related mortality (27%) than that of previous protocols. However, transplant-related mortality in these high-risk patients remains elevated. Current myeloablative BMT in adult patients is characterized by higher transplant-related toxicity due to an advanced phase of disease. Although this new approach to transplant adult patients with a reduced-dose intensity-conditioning regimen has improved thalassemia-free survival, transplant-related mortality in these high-risk patients remains elevated.

Topics: Adolescent; Adult; Azathioprine; Bone Marrow Transplantation; Busulfan; Chelation Therapy; Clinical Protocols; Combined Modality Therapy; Comorbidity; Deferoxamine; Disease-Free Survival; Erythrocyte Transfusion; Erythropoietin; Female; Follow-Up Studies; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hemosiderosis; Humans; Hydroxyurea; Immunosuppressive Agents; Iron Chelating Agents; Life Tables; Liver Cirrhosis; Male; Phlebotomy; Postoperative Complications; Survival Analysis; Thalassemia; Transfusion Reaction; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Dysregulated erythropoietin (EPO) plasma levels may play a role in the pathophysiology of chronic liver disease (CLD) because chronic anaemia is frequently observed in patients with liver cirrhosis. We aimed to identify the factors contributing to EPO regulation in patients with CLD.. Plasma EPO concentrations were correlated with clinical and laboratory parameters in 111 CLD patients and 220 healthy controls.. Anaemia, though generally mild, was common in CLD patients, and thrombocytopenia and previous bleeding episodes were observed in two-thirds of the patients. Plasma EPO levels were significantly elevated in CLD patients (P < 0.001). EPO increased according to Child's stages of cirrhosis, independently of the aetiology of CLD. EPO correlated with haemoglobin (r= -0.498, P < 0.001). Additionally, EPO independently correlated with markers of liver dysfunction, e.g. prothrombin time, albumin concentration or cholinesterase activity, and platelet count. EPO was also significantly elevated in patients with a current bleeding tendency and with prior gastrointestinal haemorrhages. EPO levels were increased in patients with impaired pulmonary function, e.g. decreased diffusion capacity, vital capacity or hyperventilation. Interestingly, plasma interleukin-6 (IL-6) concentrations positively correlated with EPO (r=0.277, P = 0.003), suggesting a possible mechanism of EPO upregulation in patients with CLD through IL-6 dependent pathways, e.g. binding of STAT transcription factors in the putative EPO promoter region.. EPO is upregulated in patients with chronic liver diseases in response to anaemia, bleeding complications, impaired pulmonary function, thrombocytopenia and liver dysfunction. IL-6 dependent pathways could be involved in mediating elevated EPO levels in CLD patients.

Topics: Adolescent; Adult; Aged; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemorrhage; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Respiratory Function Tests; Severity of Illness Index; Thrombocytopenia; Up-Regulation

To investigate the serum erythropoietin (Epo) levels in patients with chronic liver diseases and to compare to subjects with iron-deficiency anaemia and healthy controls.. We examined 31 anaemic (ALC) and 22 non-anaemic (NALC) cirrhotic patients, 21 non- anaemic subjects with chronic active hepatitis (CAH), 24 patients with iron-deficiency anaemia (ID) and 15 healthy controls. Circulating Epo levels (ELISA; R and D Systems, Europe Ltd, Abingdon, UK) and haemoglobin (Hb) concentration were determined in all subjects.. Mean+/-SD of Epo values was 26.9+/-10.8 mU/mL in ALC patients, 12.5+/-8.0 mU/mL in NALC subjects, 11.6+/-6.3 mU/mL in CAH patients, 56.4+/-12.7 mU/mL in the cases of ID and 9.3+/-2.6 mU/mL in controls. No significant difference (P>0.05) was found in Epo levels between controls, CAH and NALC patients. ALC individuals had higher Epo levels (P<0.01) than these groups whereas ID subjects had even higher levels (P<0.001) than patients suffering from ALC.. Increased Epo values in cirrhotics, are only detectable when haemoglobin was lesser than 12 g/dL. Nevertheless, this rise in value is lower than that observed in anaemic patients with iron-deficiency and appears blunted and inadequate in comparison to the degree of anaemia.

Topics: Aged; Anemia, Iron-Deficiency; Erythropoietin; Female; Hemoglobins; Hepatitis, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Regression Analysis

In patients with cirrhosis, anemia is common and is likely to be multifactorial, including decreased erythrocyte production, sequestration due to hypersplenism, hemolysis, and increased blood loss from gastrointestinal bleeding. Renal dysfunction is also common in liver disease and this may also cause anemia. However, an association between anemia and renal dysfunction has not been reported in patients with cirrhosis. Our objective was to determine whether anemia in cirrhotic patients is independently related to renal dysfunction. We conducted a retrospective chart review of patients in our institution listed for liver transplantation. We collected simultaneous data on age, hemoglobin, creatinine, albumin, liver enzymes, prothrombin time, and bilirubin. We excluded patients who were hospitalized or deceased to avoid confounding variables. Two hundred eighty-six (female n = 130) patients with a mean age of 52.8 +/- 9.7 (range, 18-73) years were studied. Renal dysfunction (creatinine > 1.2 mg/dL) was present in 55 (19%) patients, and anemia (hemoglobin < 12 g/dL) was seen in 115 (40%) patients. Anemia was more common in patients with renal dysfunction (64 versus 34%; P < 0.001) compared to those with normal renal function. Creatinine, prothrombin time, and bilirubin showed an inverse relationship (all P's < 0.001) with hemoglobin, and albumin showed a positive correlation with hemoglobin (P < 0.001). Multivariate analysis showed that creatinine (OR, 2.4; 95% CI, 1.05-5.3; P = 0.038), prothrombin time (P = 0.026), bilirubin (P = 0.035), and albumin (P = 0.001) were independent predictors of anemia. Renal dysfunction is an important cause of anemia in patients with cirrhosis. The role of erythropoietin in the management of anemia in patients with cirrhosis and renal dysfunction should be explored in prospective studies.

Topics: Adolescent; Adult; Age Distribution; Aged; Analysis of Variance; Anemia; Chronic Disease; Comorbidity; Confidence Intervals; Erythropoietin; Female; Follow-Up Studies; Humans; Incidence; Kidney Function Tests; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Odds Ratio; Probability; Renal Insufficiency; Retrospective Studies; Risk Assessment; Sex Distribution; Waiting Lists

Topics: Aged; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Carcinoma, Hepatocellular; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Hypersplenism; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Myelodysplastic Syndromes; Pancytopenia; Reticulocyte Count; Reticulocytes

Thrombocytopenia is a frequent hematological complication in patients with liver cirrhosis, but its pathogenesis is not clearly understood. We evaluated the effect of iron depletion by phlebotomy on platelet count in 62 consecutive iron overloaded patients with liver cirrhosis and thrombocytopenia. After a median follow-up of 30.2 months we observed a significant increase of platelet count in all patients (from mean baseline levels of 110.1 up to 168.22109/l at the end of follow-up, P<0.001) with platelet count normalization in 42 of them (67.7%). In addition, we observed a significant improvement of serum ALT levels (from pretreatment mean values of 126.7 up to 59.7 U/l at the end of follow-up, P<0.001) along with the reduction of serum ferritin levels and transferrin saturation during phlebotomy. Different pathogenetic mechanisms involving both humoral (erythropoietin and thrombopoietin, TPO) and physical (portal hypertension and hypersplenism) factors are here discussed to explain the platelet count increase following phlebotomy. Our results show that phlebotomy is effective not only in lowering iron overload, but also in improving liver function and thrombocytopenia in patients with liver cirrhosis.

Topics: Aged; Erythropoietin; Female; Follow-Up Studies; Humans; Hypersplenism; Hypertension; Iron Overload; Liver Cirrhosis; Male; Middle Aged; Phlebotomy; Platelet Count; Retrospective Studies; Thrombocytopenia; Thrombopoietin; Treatment Outcome

The level of plasma erythropoietin (EPO) in patients with cirrhosis is controversial. It is known that overproduction of nitric oxide (NO) plays, in part, a role for the development of peripheral arterial vasodilatation in cirrhosis with portal hypertension. It has also been hypothesized that a possible interaction is noted between endogenous EPO and NO production. The current study was undertaken to evaluate the relationship between plasma EPO levels and the severity of liver disease, hemodynamic values, renal functions, and plasma nitrate/nitrite levels in patients with cirrhosis.. The authors measured the biochemistry, plasma EPO and nitrate/nitrite levels in 67 patients with cirrhosis (Child-Pugh class A in 23 and Child-Pugh class B and C in 44) and compared their values with those in 34 healthy subjects. Systemic and splanchnic hemodynamic measurements and effective renal plasma flow were obtained from cirrhotic patients.. Plasma EPO and nitrate/nitrite levels were significantly increased in patients with cirrhosis compared with healthy subjects. Additionally, plasma EPO values were higher in cirrhotic patients with ascites or with anemia than in those without ascites or without anemia, respectively. Plasma EPO levels were positively correlated to the hepatic venous pressure gradient (HVPG) and Child-Pugh score, negatively correlated to the renal and hepatic blood flows, but were not correlated to nitrate/nitrite level and systemic vascular resistance in cirrhotic patients. Multiple regression analysis showed that HVPG and renal plasma flow were independent predictors for the elevated EPO level in cirrhotic patients.. Plasma EPO levels were increased in patients with cirrhosis compared with those in healthy subjects. The increase in plasma EPO levels is related to the degree of portal hypertension, the severity of cirrhosis and the renal plasma flow. In contrast, the EPO levels had no correlation to the nitrate/nitrite levels and systemic vascular resistance in patients with cirrhosis.

Topics: Anemia; Ascites; Blood Pressure; Cardiac Output; Erythropoietin; Hepatic Veins; Humans; Hypertension, Portal; Kidney; Liver Circulation; Liver Cirrhosis; Nitrates; Nitric Oxide; Nitrites; Renal Blood Flow, Effective; Vascular Resistance; Venous Pressure

Anemia frequently accompanies end-stage liver disease. Erythropoietin has recently been shown to be of benefit in a number of diseases complicated by anemia. We studied erythropoietin levels before and after orthotopic liver transplantation (OLT) and correlated these with the degree of anemia. Twenty-seven patients with end-stage cirrhosis who underwent OLT had preoperative and weekly postoperative serum erythropoietin levels determined by a highly sensitive radioimmunoassay. The relation of erythropoietin level to the values for hematocrit, serum creatinine, and cyclosporine and other biochemical test results was evaluated. Before transplantation, 23 patients were anemic; erythropoietin levels were appropriately elevated (72.7 +/- 37 mU/mL; normal, 10 to 15 mU/mL) for the degree of anemia (hematocrit, 33.1% +/- 1%) in 16 patients (70%). A blunted erythropoietin response to anemia was found in 7 of the anemic patients with cirrhosis (30%). After OLT, the hematocrit decreased to 29.5% +/- 0.6% at 4 weeks, with a reciprocal increase in serum erythropoietin levels to 36 +/- 5 mU/mL. Erythropoietin response appeared appropriate to the degree of anemia in 82% of the liver transplant recipients and blunted in 18%. We conclude that the ability to secrete erythropoietin in response to anemia is defective in many patients with end-stage liver disease, and a normal response may be restored after OLT. The results suggest that exogenous erythropoietin administration may be beneficial in anemic patients with cirrhosis and liver transplant recipients who have inappropriately low serum erythropoietin levels.

Topics: Adult; Anemia; Erythropoietin; Female; Hematocrit; Humans; Liver Cirrhosis; Liver Transplantation; Male; Postoperative Period

Juvenile hemochromatosis is a rare genetic disorder that causes iron overload. Clinical complications, which include liver cirrhosis, heart failure, hypogonadotropic hypogonadism and diabetes, appear earlier and are more severe than in HFE-related hemochromatosis. This disorder, therefore, requires an aggressive therapeutic approach to achieve iron depletion. We report here the case of a young Italian female with juvenile hemochromatosis who was unable to tolerate frequent phlebotomy because of coexistent ss-thalassemia trait. The patient was successfully iron-depleted by combining phlebotomy with recombinant human erythropoietin.

Topics: Adrenal Cortex Hormones; Adrenal Insufficiency; Adult; Arrhythmias, Cardiac; beta-Thalassemia; Chelation Therapy; Chromosomes, Human, Pair 1; Deferoxamine; Erythropoietin; Estrogen Replacement Therapy; Female; Hemochromatosis; Hemosiderosis; Hormone Replacement Therapy; Humans; Hypogonadism; Liver Cirrhosis; Phlebotomy; Progesterone; Recombinant Proteins

Topics: Christianity; Embolization, Therapeutic; Erythropoietin; Humans; Jehovah's Witnesses; Liver Cirrhosis; Liver Transplantation; Male; Preoperative Care; Recombinant Proteins

This study was constructed to investigate the relationship between renal anaemia and erythropoietin (EPO) concentrations in chronic renal failure (CRF) patients and to evaluate the possible role of the liver. Serum EPO levels were measured in blood samples from 20 CRF patients on hemodialysis (HD), 20 liver cirrhosis (LC) patients, 20 patients having both CRF and LC and undergoing HD, and 20 normal control subjects. Blood cell counts, iron indices (iron, total iron-binding capacity (TIBC) and ferritin), renal function (blood urea nitrogen (BUN) and creatinine), hepatic function (ALT, AST, ALP and bilirubin) investigations were carried out for all the subjects enrolled in this study. CRF patients without LC had serum EPO concentration of 6.21 +/- 0.53 mU/ml (mean +/- SE), which was significantly higher than that in patients having both CRF and LC (4.32 +/- 0.52) (p < 0.01). Both groups showed significantly lower values than the controls (12.75 +/- 0.70) (p < 0.001). LC patients with intact kidneys had significantly higher EPO level (22.70 +/- 1.70) (p < 0.001). No correlation was found between EPO level and any of the hematologic or iron indices.

Topics: Adult; Erythropoietin; Ferritins; Humans; Iron; Kidney; Kidney Failure, Chronic; Liver; Liver Cirrhosis; Male; Middle Aged

To clarify the role of thrombopoietin (c-Mpl ligand, TPO) in 'hypersplenic' thrombocytopenia, we used an enzyme-linked immunosorbent assay to examine changes in serum TPO levels accompanied with splenectomy in 6 patients with liver cirrhosis, 4 patients with gastric cancer, and 2 patients with lymphoid malignancies. We also measured serum levels of other thrombopoietic cytokines such as interleukin-6 (IL-6) and erythropoietin. Platelet counts reached a maximum at day 14 after splenectomy in all subjects. In patients with liver cirrhosis, a lower elevation of platelet counts was observed compared with that in patients with gastric cancer. Serum TPO levels gradually elevated after splenectomy and reached a maximum 3.5 days after splenectomy in noncirrhotic patients, whereas peak serum TPO levels were delayed until day 7 in the cirrhosis group. IL-6 and erythropoietin showed similar kinetics between cirrhotic and noncirrhotic patients. These findings suggest that transient thrombocytosis after splenectomy may be associated with an alteration in the site of TPO catabolism by platelets from spleen to the blood and that deterioration of TPO production may play a role in thrombocytopenia in liver cirrhosis.

Topics: Adult; Aged; Erythropoietin; Female; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Splenectomy; Thrombocytopenia; Thrombocytosis; Thrombopoietin

To observe the effects of erythropoietin or nitric oxide synthesis (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on hyperdynamic circulatory state in rats with cirrhosis.. Cirrhotic rat model was made. Cirrhotic rats were treated with NOS inhibitor L-NAME (0.5 mg.kg-1.d-1) by gavage or with erythropoietin (100 U/kg) injected subcutaneously for two weeks. The hemodynamic parameters in cirrhotic rats treated with L-NAME or with erythropoietin were determined by using 57Co-labled microsphere technique. Serum nitric oxide (NO) levels were also measured by using a fluorometric assay.. Hyperdynamic circulatory state was observed in all rats with cirrhosis. Serum NO levels in cirrhotic rats were significantly higher than that in normal controls. Hyperdynamic circulation status in cirrhotic rats treated with erythropoietin or with L-NAME was markedly attenuated. As compared with untreated-cirrhotic rats, serum NO concentration in erythropoietin-treated and L-NAME-treated cirrhotic rats were significantly lower.. L-NAME treatment could reverse the hyperdynamic circulatory state in cirrhotic rats which might be ameliorated by inactivation of overproduced NO by increasing hemoglobin with erythropoietin.

Topics: Animals; Erythropoietin; Hemodynamics; Liver Cirrhosis; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Random Allocation; Rats; Rats, Sprague-Dawley

Topics: Erythropoietin; Hematocrit; Humans; Liver Cirrhosis; Liver Diseases

Chronic anemia is frequently observed in patients affected by cirrhosis. To investigate the possible role of erythropoietin (Epo) in the pathogenesis of anemia in cirrhosis, we measured the immunoreactive Epo levels and the respective hemoglobin (Hb) concentrations in 48 anemic and nonanemic cirrhotic patients and in a control group of healthy subjects and patients with iron-deficiency anemia. Epo concentrations were determined in serum using a sensitive enzyme immunoassay. The regression curve between Epo values and Hb concentrations showed a significant inverse exponential trend both in cirrhotic patients (r = -.55; P < .0001) and controls (r = -.92; P < .0001). In a semilogarithmic plot, the line slope obtained in cirrhotic patients was significantly lower (P < .005) than that of controls, suggesting a blunt Epo response to anemia in cirrhosis. Moreover, covariance analysis showed that the Epo levels for a given degree of anemia were further reduced in the patients with a more severe disease, suggesting a close relation between cirrhosis and the mechanisms involved in the derangement of the Epo feedback system. Finally, the Epo concentrations measured in the cirrhotic patients without anemia did not significantly differ from Epo values obtained in healthy subjects. An impaired Epo response may play a role in maintaining low Hb concentrations in cirrhotic patients with anemia. However, the evidence of a residual Epo response to anemia in cirrhosis and the presence of normal basal Epo levels in nonanemic cirrhotic patients do not support an inadequate Epo secretion as one of the primary causes of anemia in cirrhosis.

Topics: Adult; Aged; Anemia; Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Feedback; Female; Hemoglobins; Humans; Liver Cirrhosis; Male; Middle Aged; Regression Analysis

The purpose of the investigation was to study the metabolism of erythropoietin (EPO) in patients with liver disease. Twelve patients with liver cirrhosis and 10 healthy volunteers were studied. The patients were moderately anemic with a hematocrit of 33 vs 42% (medians) in the volunteers. The pharmacokinetic parameters were calculated after an intravenous (i.v.) injection of 100 U/kg of recombinant human EPO. The serum EPO was measured by radioimmunoassay at regular intervals until 48 h. The median terminal elimination half life in the cirrhosis patients was 5.15 h vs 5.37 h in the control subjects. The clearance was 7.78 vs 7.52 ml/min/1.73 m2 (ns). The steady-state volume of distribution was 3.69 vs 3.09 1/1.73 m2 (ns). The estimated endogenous EPO production was significantly higher in liver cirrhosis (486 vs 290 U/d/1.73m2, p < 0.01). The basal serum EPO was significantly higher in the cirrhosis patients (43.5 vs 26.3 U/l, p < 0.01). The hematocrit correlated inversely with the basal serum EPO level in the cirrhosis patients (r = -0.63, p < 0.04). The EPO-clearance was not related to the presence of ascites, esophageal varices, or to abnormal blood chemistry. It was concluded that normal metabolism of EPO was maintained in liver cirrhosis and that the cirrhotic patients had a moderate compensatory increase of EPO production in response to anemia.

Topics: Adult; Body Weight; Erythropoietin; Female; Hematocrit; Humans; Injections, Intravenous; Liver Cirrhosis; Male; Middle Aged; Recombinant Proteins

Erythrocytosis is occasionally observed in patients with hepatocellular carcinoma (HCC). The pathogenesis of the phenomenon remains uncertain. It has been speculated that tumors produce erythropoietin (Epo), and several studies on the Epo in tumor tissues have been reported. Using a sensitive enzyme linked immunosorbent assay, we measured the serum Epo concentration in 92 HCC patients and 30 liver cirrhosis (LC) patients. The levels of Epo in normal subjects, HCC patients and LC patients were 10.5 +/- 4.1 (mean +/- SD, mU/ml), 55.6 +/- 218.0 and 18.4 +/- 19.4, respectively. Some patients with high Epo values had low levels of hemoglobin (Hb), and a scatter-gram of the two parameters was similar to that in iron deficiency anemia. In patients whose Hb levels were more than 12 g/dl, we found Epo levels of 15.0 +/- 8.8 (mean +/- SD mU/ml) and 10.3 +/- 7.7 in HCC and LC, respectively. Epo values in HCC were significantly higher than those of normal subjects (P < 0.001) and LC patients (P < 0.05), and 18.2% (10/55) had concentrations above the upper limit of the normal range. The increase was not, however, a marked one. In conclusion, as the incidence of erythrocytosis was low (2.2%) in HCC patients, the high Epo values in some patients could be related to the abnormal production of Epo by HCC.

Topics: alpha-Fetoproteins; Carcinoma, Hepatocellular; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hemoglobins; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

We have measured the serum erythropoietin concentrations in 14 patients with liver cirrhosis and in 14 patients with a hepatocellular carcinoma. Among these patients, 2 with liver cirrhosis (14.3%) and 7 with a hepatocellular carcinoma (50.0%) were found to have raised serum erythropoietin concentrations, ranging up to 40 mU/ml. Negative correlations were found between erythropoietin and the RBC, and the Hb and Ht in the cases with liver cirrhosis. In contrast, a positive correlation which was not significant was found only between the erythropoietin and the RBC in cases involving a hepatocellular carcinoma. This has suggested that the relationship between the erythropoietin and the RBC in cases of a hepatocellular carcinoma differs from the relationship seen under the usual physiological circumstances of those with liver cirrhosis.

Topics: Aged; Carcinoma, Hepatocellular; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

A case of hepatocellular carcinoma associated with polycythemia and chronic thyroiditis, is reported in a 76-year-old female. At autopsy, the liver tumor was shown to be co-existent with liver cirrhosis. A series of hematological studies including the determination of plasma erythropoietin levels, led to the conclusion that this patient's polycythemia was most likely due to an excessive production of erythropoietin by the liver tumor. Chronic thyroiditis, another combined disease, might be related to liver cirrhosis, if the formerly advocated "hepato-thyroidal syndrome" is accepted. The author reports on this patient, since prior to this case there has been no documented case report of hepatocellular carcinoma accompanying both polycythemia and chronic thyroiditis.

Topics: Aged; Carcinoma, Hepatocellular; Erythropoietin; Female; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Polycythemia; Thyroiditis, Autoimmune

Recently, a factor was discovered in the serum of hepatectomized animals which was capable of augmenting the hepatic erythropoietin response to hypoxia when injected into normal rats. This substance was localized in the liver via an in situ perfusion technique and was termed the hepatic erythropoietic factor (HEF). Patients with kidney disease, liver disease, and combined renal and hepatic disease were studied in this report. Detectable HEF levels were found in the plasma of patients with both liver and kidney disease and were highest in anephric patients with various liver diseases. However, HEF levels were negligible in normal humans or in patients manifesting renal disease with no hepatic involvement. The data suggest that HEF-induced hepatic erythropoietin synthesis may occur in humans as well as in animals.

Topics: Adult; Aged; Animals; Blood Proteins; Erythropoietin; Female; Humans; Kidney; Kidney Failure, Chronic; Liver; Liver Cirrhosis; Liver Diseases; Mice; Middle Aged; Rats

Topics: Anemia; Animals; Biliary Fistula; Constriction; Erythropoietin; Female; Humans; Iron Isotopes; Kidney; Liver; Liver Cirrhosis; Nephritis; Phenylhydrazines; Rats; Spleen; Trypan Blue

Topics: Aged; Carcinoma, Hepatocellular; Erythropoietin; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Polycythemia; Urine

Topics: Absorption; Carbon Tetrachloride Poisoning; Chelating Agents; Diet; Dietary Proteins; Epoetin Alfa; Erythropoietin; Intestine, Small; Intestines; Iron; Iron Isotopes; Liver Cirrhosis; Liver Cirrhosis, Experimental; Pharmacology; Polycythemia; Rats; Research; Toxicology