Obesity, elevated levels of fasting plasma glucose and type 2 diabetes are associated with aortic stiffness.

OBJECTIVES: Obesity and metabolic syndrome (MetS) are associated with structural and functional vascular abnormalities. MetS and its components may increase arterial stiffness and the risk of cardiovascular events. However, the relationship of MetS and its components, including obesity, with arterial stiffness is still not fully understood. SUBJECTS AND METHODS: In a group of 116 patients undergoing treatment for hypertension, we searched for the relationships between parameters of MetS and aortic stiffness expressed by pulse wave velocity (PWVAo). PWVAo was measured using an arteriograph working on the oscillometric principle, and pulse wave analysis (PWA) for noninvasive assessment of the parameters of central hemodynamics. RESULTS: From the cluster of parameters of MetS we found a significant association between body mass index (BMI) and aortic stiffness, and between fasting plasma glucose/type 2 diabetes (FPG/T2DM) and aortic stiffness. We did not find significant relationships between other components of MetS (HDL cholesterol and triglycerides) and aortic stiffness, based on the influence of hypolipidemic therapy. Arterial stiffness increased with age and was higher in females. CONCLUSION: Arterial stiffness was associated with age, sex, and MetS components (BMI and FPG/T2DM). Surprisingly, the parameters of dyslipidemia do not influence stiffness parameters, which can be explained by hypolipidemic therapy. The influence of hypolipidemic therapy should therefore be borne in mind when evaluating arterial tree function (Tab. 15, Ref. 62). Text in PDF www.elis.sk Keywords: obesity, fasting plasma glucose, type 2 diabetes, aortic stiffness, metabolic syndrome, arterial hypertension, cardiovascular risk.

Questionnaire for risk factors of alcoholic and nonalcoholic fatty liver disease.

OBJECTIVES: Non-communicable diseases are estimated to account for 90 % of total deaths and 19 % of premature deaths in Slovakia. Major preventable risk factors of premature mortality are overweight, obesity and alcohol consumption. BACKGROUND: Screening of risk factors related to alcoholic and nonalcoholic fatty liver diseases (AFLD and NAFLD, respectively) in Slovak outpatients with liver disease. METHODS: A total group of 923 patients, aged 19-91 years were included in the study. Self-administered anonymous questionnaires (Q) were filled in by them. Twelve questions were included relating to age, gender, education, BMI, intake of vegetable, fruit, fish, alcohol, and coffee, as well as to smoking and physical exercise. RESULTS: Overweight/obesity was detected in 59 % of patients, insufficient fiber intake in 87 % of patients, insufficient fish intake in 85 % of patients, and insufficient physical exercise in 68 % of patients. BMI over 25 together with the risk of alcohol consumption was present in 68 % of patients. Smoking was present in 19 % of patients and insufficient coffee intake (from its hepatoprotective point of view) was in 35 % of patients. A total proportion of 75 % of patients were at risk for NAFLD. The risk of alcohol consumption was present in 64 % of patients. CONCLUSIONS: An anonymous questionnaire is a useful screening tool for searching for the risks of NAFLD and AFLD in general practice. Recommendation of a screening schedule for general practitioners is implemented (Tab. 2, Fig. 4, Ref. 36).

Serum butyrylcholinesterase/HDL-cholesterol ratio and atherogenic index of plasma in patients with fatty liver disease.

Cardiovascular diseases on an atherosclerotic basis are a serious health problem. Atherosclerosis is a multifactorial pathological process with complex pathogenesis. Its origin and development is conditioned by a set of several risk factors. Changes in the spectrum of lipoproteins are one of the well-known, serious risk factors for cardiovascular disease. The results of several authors showed, that the examination of the ratio of some lipoproteins can provide more accurate information about the cardiovascular risk in a given individual than the individual lipid parameters alone. Non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic hepatopathy. The aim of our study was to examine lipoprotein ratios - atherogenic index of plasma (AIP) and butyrylcholinesterase/ HDL-cholesterol ratio - in patients with NAFLD and to evaluate their changes in relation to the severity of hepatic steatosis. The study group consisted of 64 patients with hepatic steatosis, 32 men and 32 women. Patients were examined for fatty liver index (FLI), with FLI values above 60.0 signaling the presence of steatosis. From the biochemical parameters, we examined the serum concentrations of total cholesterol, HDL- and LDL-cholesterol, triacylglycerols and butyrylcholinesterase activity in patients with fatty liver disease. As the results of our study showed, both basic lipid parameters - total cholesterol and triacylglycerols - were increased in patients with hepatic steatosis compared to the values in the control group (Chol: 3,59 ± 0,16 vs. 5,14 ± 0,14 mmol/l; TAG: 0,85 ± 0,06 vs. 1,86 ± 0,14 mmol/l). Both investigated lipoprotein ratios - AIP and the BChE / HDL-cholesterol ratio were also significantly increased in patients with liver steatosis (AIP: -0,191 ± 0,04 vs. 0,157 ± 0,04; BChE/HDL-C: 3171 ± 123 vs. 4602 ± 291). The value of the BChE/HDL-cholesterol ratio correlated well with the total cholesterol/HDL cholesterol ratio (correl.coeff. 0,802) as well as with the atherogenic index of plasma (correl.coeff. 0,702). The findings of elevated AIP and BChE/HDL-C ratios confirmed the hypothesis of an increased risk of cardiovascular disease in patients with fatty liver disease. The finding of a significant positive correlation between AIP and BChE/HDL-C on the one hand and fatty liver index (FLI) on the other hand suggests that cardiovascular risk increases with the severity of steatotic liver injury.

Pharmacokinetics and tolerability of semaglutide in people with hepatic impairment.

AIMS: To investigate whether the pharmacokinetic characteristics of semaglutide were altered in people with hepatic impairment, assessed using Child-Pugh criteria, vs those with normal hepatic function. METHODS: In this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ClinicalTrials.gov ID NCT02210871), four groups of participants with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n = 7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞ ). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-group ratio (hepatic impairment/normal function) was within the interval 0.70 to 1.43. RESULTS: Semaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal function of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal function 1.02 (90% CI 0.93, 1.12), and severe impairment/normal function 0.97 (90% CI 0.84, 1.12). The maximum plasma semaglutide concentration (Cmax ) did not appear to be influenced by hepatic function, with mild impairment/normal function treatment ratios of 0.99 (90% CI 0.80, 1.23), moderate impairment/normal function 1.02 (90% CI 0.88, 1.18) and severe impairment/normal function 1.15 (90% CI 0.89, 1.48; sensitivity analysis excluding one extreme semaglutide concentration: 1.05 [90% CI 0.88, 1.25]). In all, 10 participants reported 12 mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed. CONCLUSIONS: Semaglutide exposure did not appear to be affected by hepatic impairment, suggesting that dose adjustment may not be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec.

BACKGROUND AND OBJECTIVE: Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. METHODS: Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose. RESULTS: The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure. CONCLUSIONS: The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.

The Effect of Hepatic Impairment on the Pharmacokinetics of Intravenously Administered Felcisetrag (TAK-954).

Felcisetrag (formerly known as TAK-954) is a selective serotonin receptor agonist under investigation for use in patients with postoperative gastrointestinal dysfunction. The safety, tolerability, and pharmacokinetics (PK) of intravenous (i.v.) felcisetrag have been studied, but little is known about the effect of hepatic impairment on the PK of the drug. This phase 1, non-randomized, open-label study compared the PK of a single 60-minute i.v. infusion of felcisetrag between healthy individuals (n = 8) and patients with moderate (n = 10) or severe (n = 7) hepatic impairment. The primary study end points were the total and free maximum observed plasma concentration of felcisetrag at the end of infusion (Cmax ), area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUClast ), and AUC from time 0 to infinity (AUCinf ). Concentration-time profiles of felcisetrag were similarly shaped between groups but revealed lower concentrations of total plasma felcisetrag with increasing severity of hepatic impairment, whereas concentrations of free felcisetrag increased. The ratios of AUClast and AUCinf for patients with severe hepatic impairment were up to 29.3% lower for total felcisetrag and up to 29.2% higher for free felcisetrag than found in healthy individuals (P < .05). Infusions were well tolerated with no discontinuations, severe adverse events, or deaths during the study. Overall, the effect of hepatic impairment on exposure to felcisetrag was minimal, suggesting that dose adjustment may be unnecessary in patients with hepatic impairment.

Chronic hepatitis C virus infection in the Czech Republic and Slovakia: an analysis of patient and virus characteristics.

OBJECTIVES: The MOSAIC study gathered data on chronic hepatitis C virus (HCV) infection and its treatment in various countries worldwide. Here we summarise patient and HCV characteristics in the Czech Republic and Slovakia. METHODS: MOSAIC was an observational study that included patients with chronic HCV infection untreated at the time of enrolment. Study collected and descriptively analysed patient demographics, disease stage and viral characteristics. Data were collected between February 2014 to October 2014. RESULTS: Among 220 patients enrolled, 51.4% were treatment-naïve. The most prevalent HCV genotype was G1 (78.4%), followed by G3 (19.7%). Higher prevalence of G1 was found in treatment-experienced patients (94.3%) compared to treatment-naïve (63.4%). Most participants (67.7%) presented viral RNA load of ≥ 800,000 IU/mL. Liver cirrhosis was reported in 24.5% of patients. Higher HCV RNA load and duration of HCV infection correlated with the degree of liver fibrosis. Anti-HCV interferon-based treatments were initiated in 88.2% of participants. CONCLUSIONS: The study confirmed significant changes in the HCV genotypes partition with G3 genotype rapidly increasing in both countries, with possible impact on the WHO eradication initiative and treatment selection.

Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. It represents a range of disorders, including simple steatosis, nonalcoholic steatohepatitis (NASH), and liver cirrhosis, and its prevalence continues to rise. In some cases, hepatocellular carcinoma (HCC) may develop. The develop;ment of non-invasive diagnostic and screening tools is needed, in order to reduce the frequency of liver biopsies. The most promising methods are those able to exclude advanced fibrosis and quantify steatosis. In this study, new perspective markers for inflammation, oxidative stress, apoptosis, and fibrogenesis; emerging scoring models for detecting hepatic steatosis and fibrosis; and new genetic, epigenetic, and multiomic studies are discussed. As isolated biochemical parameters are not specific or sensitive enough to predict the presence of NASH and fibrosis, there is a tendency to use various markers and combine them into mathematical algorithms. Several predictive models and scoring systems have been developed. Current data suggests that panels of markers (NAFLD fibrosis score, Fib-4 score, BARD score, and others) are useful diagnostic modalities to minimize the number of liver biopsies. The review unveils pathophysiological aspects related to new trends in current non-invasive biochemical, genetic, and scoring methods, and provides insight into their diagnostic accuracies and suitability in clinical practice.

Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment.

Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment.

Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis.

BACKGROUND AND AIM: Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis. METHODS: An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24). RESULTS: In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred. CONCLUSIONS: Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.

Insulin degludec: pharmacokinetic properties in subjects with hepatic impairment.

BACKGROUND AND OBJECTIVE: Insulin degludec is a basal insulin with a slow and distinct absorption mechanism resulting in an ultra-long, flat, and stable pharmacokinetic profile in patients with diabetes mellitus. The aim of this study was to examine the effect of hepatic impairment on the single-dose pharmacokinetics of insulin degludec. METHODS: Twenty-four subjects, allocated to one of four groups (n=6 per group) based on level of hepatic impairment (normal hepatic function, Child-Pugh grade A, B, or C), were administered a single subcutaneous dose of 0.4 U/kg insulin degludec. Blood samples up to 120 h post-dose and fractionated urine samples were collected to measure pharmacokinetic parameters. RESULTS: No difference was observed in pharmacokinetic parameters [area under the 120-h serum insulin degludec concentration-time curve (AUC120 h), maximum insulin degludec concentration (C max), and apparent clearance (CL/F)] for subjects with impaired versus normal hepatic function after a single dose of insulin degludec. The geometric mean [coefficient of variation (CV) %] AUC120 h values were 89,092 (16), 83,327 (15), 88,944 (23), and 79,846 (19) pmol·h/L for normal hepatic function and mild, moderate, and severe hepatic impairment, respectively. Simulated steady-state insulin degludec pharmacokinetic profiles showed an even distribution of exposure across a 24-h dosing interval regardless of hepatic function status. CONCLUSIONS: The ultra-long pharmacokinetic properties of insulin degludec were preserved in subjects with hepatic impairment and there were no statistically significant differences in absorption or clearance compared with subjects with normal hepatic function.

Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients.

BACKGROUND AND AIMS: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of HCC. Miravirsen targets miR-122 and resulted in a dose dependent and prolonged decrease of HCV RNA levels in chronic hepatitis C patients. The aim of this study was to establish the sustained virological response rate to peginterferon (P) and ribavirin (R) following miravirsen dosing and to assess long-term safety in patients treated with miravirsen. METHODS: In this multicenter, retrospective follow-up study we included 36 treatment naïve patients with chronic hepatitis C genotype 1 who received five weekly subcutaneous injections with miravirsen or placebo over a 29-day period in a phase 2a study. Patients were offered PR therapy 3weeks (3mg/kg group) or 6weeks (5 or 7mg/kg group) after completion of miravirsen or placebo dosing. RESULTS: PR therapy was started in 14/36 patients of whom 12 had received miravirsen. SVR was achieved in 7/12 patients previously dosed with miravirsen. All patients dosed with 7mg/kg miravirsen who were subsequently treated with PR achieved SVR. One patient had a prolonged undetectable HCV RNA period from week 14 to week 29 after baseline without subsequent antiviral therapy and relapsed thereafter. None of the patients treated with anti-miR-122 developed HCC or other liver-related complications. CONCLUSION: No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials.

Effect of renal or hepatic impairment on the pharmacokinetics of mirabegron.

BACKGROUND AND OBJECTIVES: Mirabegron, a selective ß3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated. METHODS: Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites. RESULTS: Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects. CONCLUSION: Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.

The effect of severe hepatic impairment on the pharmacokinetics and haematological response of C.E.R.A.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.

Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis - amelioration by liver transplantation.

BACKGROUND/AIMS: Modification by advanced glycation renders macromolecules susceptible to elimination in the liver via scavenger receptors. Thus, in advanced liver disease an accumulation of advanced glycation end products (AGEs) in circulation might occur, due to the reduction of effective liver mass. METHODS: Plasma AGE levels (fluorescent AGEs-AGE-Fl and N(epsilon)-carboxymethyllysine - CML) were determined in 51 patients with liver cirrhosis (Ci) and 19 healthy controls. Five patients were followed 36 months after liver transplantation. RESULTS: In cirrhotic patients, markedly elevated concentrations of AGEs were revealed (AGE-Fl: control, 0.3+/-0.01 x 10(5) AU, Ci: 1.06+/-0.06 x 10(5) AU, P<0.01; CML, control: 431.7+/-16.3 ng/ml, Ci: 647.6+/-258.5, P<0.01). CML levels correlated with the severity of liver disease, as determined by clinical score (r=0.663, P<0.001), albumin level (r=0.704, P<0.001) and monoethylglycinexylide test (r=0.852, P<0.01). Reduced renal function contributed to the rise of CML in proportion to the degree of renal impairment. Liver transplantation resulted in about 50% decline of CML levels within 3 months, while impairment of renal function still persisted, underlying the central role of the liver for AGE removal. CONCLUSIONS: In liver Ci, hepatic removal of AGEs is impaired. With regard to the toxicity of AGEs, their accumulation could be of pathophysiological relevance.