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1.
Hepatol Res ; 49(2): 201-211, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30248213

ABSTRACT

AIMS: Endocrinological abnormalities, including low testosterone levels, are prevalent in cirrhosis. We assessed sexual hormone status in regard to hemodynamic abnormalities and its impact on hepatic decompensation and survival. METHODS: Males with cirrhosis were prospectively included in this study since 2010. Sexual hormones including bioavailable testosterone, total testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and sex hormone-binding globulin as well as Child-Pugh score, Model for End-stage Liver Disease (MELD) score, and hepatic venous pressure gradient were recorded. Sarcopenia was also assessed in patients with available computed tomography scans. Clinical follow-up for hepatic decompensation, liver transplantation, and death was recorded until May 2017. RESULTS: One hundred fourteen male cirrhotic patients were included: age 55 ± 9.4 years, MELD 13.5 (range, 7-20.7). Etiologies were alcoholic liver disease in 61(53.5%) patients, viral in 30 (26.3%) patients, and other in 23 (20.2%). Child-Pugh scores were A in 32 (28.1%) patients, B in 48 (42.1%), and C in 34 (29.8%). Levels of bioavailable testosterone and total testosterone decreased with advanced Child-Pugh score (P < 0.001 and P < 0.001) whereas prolactin increased (P = 0.002). Median bioavailable testosterone (0.8 ng/mL [0.1-2] vs. 1.68 ng/mL [0.07-2.65]; P = 0.004) and total testosterone (2.7 ng/mL [0.23-12.34] vs. 7 ng/mL [0.25-10]; P = 0.041) levels were lower in patients with severe portal hypertension (hepatic venous pressure gradient >12 mmHg). Median bioavailable testosterone (0.25 ng/mL [0.07-1.7] vs. 0.97 ng/mL [0.15-2.74)]; P = 0.017) and total testosterone levels (1.28 ng/mL [0.25-7.32] vs. 4.32 ng/mL [0.43-13.47]; P = 0.031) were significantly lower in sarcopenic patients. Median follow-up was 13 months (0.2-75 months) and liver-related events were recorded in 46 patients (40.4%; death, 31 [27.2%]). Low total testosterone was associated with an increased risk for hepatic decompensation and/or death, even after adjusting for Child-Pugh score, MELD, and other relevant factors (Child-Pugh score model: hazard ratio 2.503, 95% confidence interval, 1.214-5.157, P = 0.013; MELD model: hazard ratio 3.065, 95% confidence interval, 1.523-6.169, P = 0.002). CONCLUSION: In parallel to increasing severity of cirrhosis, levels of testosterone decline whereas prolactin levels increase. However, low testosterone levels are independently associated with a higher risk for hepatic decompensation and mortality.

2.
Liver Int ; 38(8): 1427-1436, 2018 08.
Article in English | MEDLINE | ID: mdl-29368385

ABSTRACT

BACKGROUND: Although several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function-5 (IIEF-5) is a well-validated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis. METHODS: In this prospective study, erectile dysfunction was defined as: absent (>21 IIEF-5-points), mild (12-21) and severe (5-11). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded. RESULTS: Among n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 ± 9 years; model for end-stage liver disease score (MELD): 12.7 ± 3.9; Child-Pugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mild-to-moderate and moderate-to-severe erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). Child-Pugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, beta-blocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.16-34.85]; P = .033), diabetes (OR: 7.40 [1.31-41.75]; P = .023), MELD (OR: 1.19 [1.03-1.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.002-1.23]; P = .045) were independent risk factors for the presence of erectile dysfunction. CONCLUSION: About two-thirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.


Subject(s)
Erectile Dysfunction/diagnosis , Erectile Dysfunction/etiology , Liver Cirrhosis/complications , Liver/physiopathology , Adult , Austria , Diabetes Complications , Humans , Hypertension, Portal/complications , Liver Function Tests , Logistic Models , Male , Middle Aged , Prevalence , Prospective Studies , Risk Factors , Severity of Illness Index
3.
J Appl Physiol (1985) ; 122(5): 1249-1254, 2017 May 01.
Article in English | MEDLINE | ID: mdl-28008098

ABSTRACT

B-type natriuretic peptide (BNP) is a hormone released by the heart in response to volume load and exerts natriuretic properties. It is clinically used as a diagnostic and prognostic biomarker and investigated as a pharmacological agent in the therapy of heart failure. Here we investigate the changes in pituitary, adrenal, and thyroid hormones in response to BNP administration in a randomized single-blinded crossover study conducted in ten healthy men aged 21-29 yr. Participants received in two study sessions a continuous intravenous infusion during 4 h (once placebo and once 3 pmol·kg-1·min-1 BNP) and remained in supine position throughout the study. Circulating concentrations of pituitary, adrenal, and thyroid hormones, heart rate, and blood pressure were measured at baseline and hourly afterwards. BNP prevented the physiological decrease in cortisol during the late morning hours leading to elevated serum cortisol levels (P = 0.022) and increased circulating epinephrine and norepinephrine concentrations (P = 0.018 and P = 0.036, respectively). These hormone changes were accompanied by an increase in heart rate (P = 0.019) but no differences in blood pressure. Taken together, the impact of BNP on the endocrine system extends beyond the well-known inhibition of the renin-angiotensin-aldosterone system and includes increased adrenergic activity and cortisol concentrations. This neuroendocrine activation might impact the outcome of therapeutical BNP administrations and should be further investigated in conditions associated with increased BNP secretion.NEW & NOTEWORTHY The heart hormone B-type natriuretic peptide (BNP) is increased in patients with heart failure, where it is thought to have beneficial effects by reducing the preload. Here we report that intravenous administration of BNP in men leads to increases in adrenal hormones cortisol, epinephrine, and norepinephrine. Cortisol and catecholamine levels are independent predictors of increased cardiovascular mortality risk; therefore, drugs targeting the BNP system should be evaluated regarding their effects on the neuroendocrine activation accompanying heart failure.


Subject(s)
Catecholamines/blood , Hydrocortisone/blood , Natriuretic Peptide, Brain/blood , Adrenal Glands/physiology , Adult , Blood Pressure/physiology , Cross-Over Studies , Epinephrine/blood , Healthy Volunteers , Heart Rate/physiology , Humans , Male , Norepinephrine/blood , Pituitary Hormones/blood , Renin-Angiotensin System/physiology , Single-Blind Method , Thyroid Gland/physiology , Young Adult
4.
World J Urol ; 33(3): 315-21, 2015 Mar.
Article in English | MEDLINE | ID: mdl-24798455

ABSTRACT

PURPOSE: To evaluate the prevalence of lower urinary tract symptoms (LUTS) in men with liver cirrhosis. METHODS: In total, 128 men with known liver cirrhosis were prospectively evaluated using the validated German version of the International Prostate Symptom Score (IPSS) questionnaire. In parallel, all men underwent a detailed examination including medical history; physical examination; Child-Pugh liver function score (CPS) assessment; and measurement of blood levels of prostate-specific antigen (PSA), total and free testosterone, sexual hormone-binding globulin (SHBG), prolactin, luteotropic hormone (LH), and follicle-stimulating hormone (FSH). RESULTS: Mean patient age and mean IPSS was 56 ± 9 years and 8 ± 6, respectively. Mild (IPSS: 1-7), moderate (IPSS: 8-19), and severe (IPSS: 20-35) LUTS were present in 60.2 % (77/128), 31.3 % (40/128), and 7.0 % (9/128) of the patients, respectively. Storage symptoms increased with the CPS (p = 0.04). Voiding symptoms and overall IPSS did not differ between the CPS groups (p = 0.93 and p = 0.67). No correlation was found between ascites volume and IPSS, storage symptoms, voiding symptoms, or quality of life (QoL) (p = 0.46, p = 0.26, p = 0.81, p = 0.87). From CPS groups A to C, mean PSA levels (p = 0.04), total and free testosterone levels (p < 0.001 and p < 0.001), and SHBG levels decreased (p = 0.03); however, prolactin levels increased (p = 0.03). LH and FSH levels did not differ between the CPS groups (p = 0.15 and p = 0.35). CONCLUSIONS: Men with liver cirrhosis commonly have LUTS, with a predominance of storage symptoms. Liver cirrhosis may also affect PSA-based prostate cancer risk assessment. Accurate diagnosis and therapy strategies are warranted to improve the QoL of these patients.


Subject(s)
Liver Cirrhosis/complications , Liver Cirrhosis/physiopathology , Lower Urinary Tract Symptoms/epidemiology , Severity of Illness Index , Adult , Aged , Cohort Studies , Humans , Liver Cirrhosis/blood , Liver Function Tests , Lower Urinary Tract Symptoms/blood , Male , Middle Aged , Prevalence , Prolactin/blood , Prospective Studies , Risk Factors , Surveys and Questionnaires , Testosterone/blood
5.
J Hepatol ; 58(5): 911-21, 2013 May.
Article in English | MEDLINE | ID: mdl-23262249

ABSTRACT

BACKGROUND & AIMS: We evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment. METHODS: Hepatic venous pressure gradient (HVPG) was measured prior to and under NSBB treatment. Gastroduodenal and intestinal permeability was assessed by the sucrose-lactulose-mannitol (SLM) test. Anti-gliadin and anti-endomysial antibodies were measured. Levels of LPS-binding protein (LBP) and interleukin-6 (IL-6) were quantified by ELISA, and NOD2 and toll-like receptor 2 (TLR2) polymorphisms were genotyped. RESULTS: Fifty cirrhotics were included (72% male, 18% ascites, 60% alcoholic etiology). Abnormal gastroduodenal and intestinal permeability was found in 72% and 59% of patients, respectively. Patients with severe portal hypertension (HVPG ≥20 mm Hg; n=35) had increased markers of gastroduodenal/intestinal permeability (urine sucrose levels p=0.049; sucrose/mannitol ratios p=0.007; intestinal permeability indices p=0.002), and bacterial translocation (LBP p=0.002; IL-6 p=0.025) than patients with HVPG <20 mm Hg. A substantial portion of patients showed elevated levels of anti-gliadin antibodies (IgA: 60%, IgG: 34%) whereas no anti-endomysial antibodies were detected. A significant correlation of portal pressure (i.e., HVPG) with all markers of gastroduodenal/intestinal permeability and with LBP and IL-6 levels was observed. NOD2 and TLR2 risk variants were associated with abnormal intestinal permeability and elevated markers of bacterial translocation. At follow-up HVPG measurements under NSBB, we found an amelioration of gastroduodenal/intestinal permeability and a decrease of bacterial translocation (LBP - 16% p=0.018; IL-6 - 41% p<0.0001) levels, which was not limited to hemodynamic responders. Abnormal SLM test results and higher LBP/IL-6 levels were associated with a higher risk of variceal bleeding during follow-up but not with mortality. CONCLUSIONS: Abnormal gastroduodenal/intestinal permeability, anti-gliadin antibodies, and bacterial translocation are common findings in cirrhotic patients and are correlated with the degree of portal hypertension. NSBB treatment ameliorates gastroduodenal/intestinal permeability and reduces bacterial translocation partially independent of their hemodynamic effects on portal pressure, which may contribute to a reduced risk of variceal bleeding.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Carrier Proteins/blood , Cell Membrane Permeability/drug effects , Interleukin-6/blood , Intestinal Absorption/drug effects , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Membrane Glycoproteins/blood , Acute-Phase Proteins , Adult , Aged , Bacterial Translocation/drug effects , Bacterial Translocation/physiology , Cell Membrane Permeability/physiology , Comorbidity , Female , Follow-Up Studies , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Hypertension, Portal/drug therapy , Hypertension, Portal/epidemiology , Hypertension, Portal/metabolism , Intestinal Absorption/physiology , Kaplan-Meier Estimate , Lactulose/metabolism , Liver Cirrhosis/epidemiology , Male , Mannitol/metabolism , Middle Aged , Sucrose/metabolism
6.
Gut ; 62(11): 1634-41, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23250049

ABSTRACT

OBJECTIVE: Non-selective ß-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥ 20% or to values <12 mm Hg). DESIGN: Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80-160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25-50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. RESULTS: 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): -19 ± 10% versus -12 ± 11% (p<0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. CONCLUSIONS: Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Carbazoles/therapeutic use , Esophageal and Gastric Varices/prevention & control , Gastrointestinal Hemorrhage/prevention & control , Liver Cirrhosis/complications , Propanolamines/therapeutic use , Adrenergic beta-Antagonists/administration & dosage , Adult , Aged , Carbazoles/administration & dosage , Carvedilol , Dose-Response Relationship, Drug , Esophageal and Gastric Varices/etiology , Esophageal and Gastric Varices/physiopathology , Female , Follow-Up Studies , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/physiopathology , Hemodynamics/drug effects , Humans , Kaplan-Meier Estimate , Ligation , Liver Cirrhosis/physiopathology , Male , Middle Aged , Propanolamines/administration & dosage , Propranolol/therapeutic use , Treatment Failure , Treatment Outcome
7.
Platelets ; 23(5): 352-8, 2012.
Article in English | MEDLINE | ID: mdl-22098110

ABSTRACT

Erythropoietin (EPO) enhances formation of red blood cells and also affects thrombopoiesis and platelet function. We hypothesized that the effect of EPO may be reflected by changes in thromboxane B2 (TXB2) and endothelial cell function. Six male and six female subjects received recombinant human epoetin alpha (Erypo®) intravenously (300 U/kg). Biomarker levels were assessed at baseline and 4, 24, 48 and 72 hours after infusion. Epoetin alpha increased TXB2 levels by 140%, which reached significance at 48 hours (6.6 ± 5 ng/ml vs. 15 ± 9 ng/ml; p = 0.044) and remained at that level at 72 hours. In line, epoetin alpha increased E-selectin levels by 25% already at 24 hours (39 ± 21 ng/ml vs. 49 ± 26 ng/ml; p < 0.001) which stayed at this level until 72 hours (p < 0.001). The raise in platelet activation markers corresponded to an 88% increase in reticulocyte count (43 ± 10 × 10(9)/l vs. 81 ± 17 × 10(9)/l; p < 0.001) and a 9% increase in platelet count at 72 hours (224 ± 45 × 10(9)/l vs. 244 ± 52 × 10(9)/l; p = 0.005). Thrombomodulin and von Willebrand factor concentrations were not significantly altered by epoetin alpha. Interestingly, gender differences in the baseline levels of E-selectin and thrombomodulin were observed. E-selectin and thrombomodulin levels were doubled in men compared to women (51 ± 24 and 28 ± 10 ng/ml; p = 0.025 and 30 ± 5 ng/ml vs. 16 ± 5 ng/ml; p = 0.002, respectively). EPO increases TXB2 serum levels and soluble E-selectin. Further studies are needed to investigate whether these markers might be useful for estimation of thromboembolic risk during EPO-therapy and whether inhibition of thromboxane formation may lower thrombotic complications during EPO treatment: NCT01392612.


Subject(s)
Blood Platelets/drug effects , Erythropoietin/pharmacology , Biomarkers/blood , Blood Platelets/metabolism , Epoetin Alfa , Female , Humans , Male , Platelet Activation/drug effects , Prospective Studies , Recombinant Proteins/pharmacology , Reference Values , Young Adult
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