45CaCl2 autoradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia

In experimental hepatic encephalopathy and hyperammonemia, extracellular levels of glutamate are increased in hippocampus and cerebral cortex. It has been suggested that overstimulation of glutamate receptors causes a pathological entry of calcium into neurons via receptor-operated (NMDA- and AMPA-type) or voltage-dependent calcium channels leading to calcium overload and cell death. Neurodegeneration as a result of exposure to excitotoxins, including glutamate, can be localized and quantified using45CaCl2 autoradiography. This approach was used to study cerebral calcium accumulation in rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced in 6 rabbits, acute hyperammonemia in 4 rabbits; 4 control rabbits received sodium-potassium-acetate. At the start of the experiment 500 µCi45CaCl2 was given intravenously. After development of severe encephalopathy, the animals were killed by decapitation. All rabbits with acute liver failure or acute hyperammonemia developed severe encephalopathy, after 13.2±1.7 and 19.3±0.5 hours respectively (mean±SEM). Plasma ammonia levels were 425±46 and 883±21 µmol/l, respectively (p<0.05). Control rabbits maintained normal plasma ammonia levels (13±5 µmol/l), demonstrated normal behaviour throughout the study and were sacrificed after 16 hours.45Ca2+-autoradiograms of 40 µm brain sections were analyzed semiquantitatively using relative optical density and computerized image analysis. As compared to background levels45Ca was not increased in hippocampus or any other brain area of rabbits with severe encephalopathy from acute liver failure or acute hyperammonemia. This suggests that, despite increased extracellular brain glutamate levels in these conditions, glutamate neurotoxicity was not important for the development of encephalopathy in these rabbits

Sex-specific normal values and determinants of infrarenal abdominal aortic diameter among non-aneurysmal elderly population

To establish age- and sex-specific distribution of the infrarenal abdominal aortic diameters (IAD) among non-aneurysmal elderly population and to investigate the associations between traditional cardiovascular risk factors and IAD in men and women. We included 4032 participants (mean age 67.2 years; 60.4% women) from the population-based Rotterdam Study, free of cardiovascular disease, who underwent IAD ultrasound assessment between 2009–2014. Linear regression analysis was used to identify determinants of IAD. The medians (inter-quartile range) of absolute IAD and body surface area (BSA)-adjusted IAD were 17.0 (15.0–18.0) mm and 9.3 (8.5–10.2) mm for women and 19.0 (18.0–21.0) mm and 9.4 (8.6–10.3) mm for men, respectively. There was a non-linear relationship between age and IAD. IAD increased steeply with advancing age and up to 70 years. After around 75 years of age, the diameter values reached a plateau. Waist circumference and diastolic blood pressure were associated with larger diameters in both sexes. Body mass index [Effect estimate (95% CI): 0.04 (0.00 to 0.08)], systolic blood pressure [− 0.01(− 0.02 to 0.00)], current smoking [0.35 (0.06 to 0.65)], total cholesterol levels [− 0.21 (− 0.31 to − 0.11)], and lipid-lowering medication [− 0.43 (− 0.67 to − 0.19)] were significantly associated with IAD in women. Sex differences in IAD values diminished after taking BSA into account. The increase in diameters was attenuated after 70 years. Differences were observed in the associations of several cardiovascular risk factors with IAD among men and women.</p

Sex-specific normal values and determinants of infrarenal abdominal aortic diameter among non-aneurysmal elderly population

To establish age- and sex-specific distribution of the infrarenal abdominal aortic diameters (IAD) among non-aneurysmal elderly population and to investigate the associations between traditional cardiovascular risk factors and IAD in men and women. We included 4032 participants (mean age 67.2 years; 60.4% women) from the population-based Rotterdam Study, free of cardiovascular disease, who underwent IAD ultrasound assessment between 2009–2014. Linear regression analysis was used to identify determinants of IAD. The medians (inter-quartile range) of absolute IAD and body surface area (BSA)-adjusted IAD were 17.0 (15.0–18.0) mm and 9.3 (8.5–10.2) mm for women and 19.0 (18.0–21.0) mm and 9.4 (8.6–10.3) mm for men, respectively. There was a non-linear relationship between age and IAD. IAD increased steeply with advancing age and up to 70 years. After around 75 years of age, the diameter values reached a plateau. Waist circumference and diastolic blood pressure were associated with larger diameters in both sexes. Body mass index [Effect estimate (95% CI): 0.04 (0.00 to 0.08)], systolic blood pressure [− 0.01(− 0.02 to 0.00)], current smoking [0.35 (0.06 to 0.65)], total cholesterol levels [− 0.21 (− 0.31 to − 0.11)], and lipid-lowering medication [− 0.43 (− 0.67 to − 0.19)] were significantly associated with IAD in women. Sex differences in IAD values diminished after taking BSA into account. The increase in diameters was attenuated after 70 years. Differences were observed in the associations of several cardiovascular risk factors with IAD among men and women.</p

Baseline anti-NS4a antibodies in combination with on-treatment quantitative HCV-RNA reliably identifies nonresponders to pegylated interferon-ribavirin combination therapy after 4 weeks of treatment

Background Early detection of nonresponders to hepatitis C therapy limits unnecessary exposure to treatment and its side-effects. A recent algorithm combining baseline anti-NS4a antibodies and on-treatment quantitative PCR identified nonresponders to a combination of interferon and ribavirin after 1 week of treatment. Aim To validate a stopping rule based on baseline anti-NS4a antibody levels and early on-treatment virological response in treatment-naive genotype 1 chronic hepatitis C patients treated with the current standard pegylated interferon and ribavirin combination therapy. Methods Eighty-nine genotype 1 patients from the Dynamically Individualized Treatment of hepatitis C Infection and Correlates of Viral/Host dynamics Study treated for 48 weeks with standard 180 mu g pegylated interferon (PEG-IFN)-alpha-2a (weekly) and ribavirin 1000-1200mg (daily) were analysed. Baseline anti-NS4a antibody enzyme-linked immunosorbent assay (NS4a AA 1687-1718) was performed on pretreatment serum. Hepatitis C virus-RNA was assessed at days 0, 1, 4, 7, 8, 15, 22, 29, weeks 6, 7, 8, 10, 12 and 6 weekly thereafter until end of treatment. Multiple regression logistic analysis was performed. Results Overall 54 of 89 (61%) patients achieved sustained virological response. A baseline anti-NS4a antibody titre less than 1/1250 correlated with absence of favourable initial viral decline according to variable response types (P=0.015). The optimal algorithm was developed using the combination of the absence of anti-NS4a Ab (= 100.000 IU/ml at week 4. This algorithm has a specificity of 43% and negative predictive value of 100% to detect nonresponse to standard PEG-IFN-alpha-2a and ribavirin therapy at fourth week of therapy (intention-to-treat analysis). Conclusion The decision to stop the therapy in genotype 1 chronic hepatitis C patients treated with PEG-IFN-alpha-2a and ribavirin can be confidently made after 4 weeks of treatment based on the absence of baseline anti-NS4a Ab and a week-4 hepatitis C virus-RNA above 100.000 IU/ml. Eur J Gastroenterol Hepatol 22:1443-1448 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Serum levels of caspase-cleaved cytokeratin 18 (CK18-Asp396) predict severity of liver disease in chronic hepatitis B

Background and aim: Caspase-cleaved cytokeratin 18 (CK18-Asp396) is a potential clinically useful biomarker in liver disease as it is released from hepatocytes during apoptosis. In this study, we investigated serum CK18-Asp396 levels in chronic hepatitis B (CHB). Patients and methods: Overall, 163 patients with CHB were included. Serum CK18-Asp396 levels were determined by enzyme-linked immunosorbent assay (ELISA), and results were related to steatosis grade, histological activity index, inflammation score, and METAVIR fibrosis grade as well as to viral load, serum levels of liver enzymes, and albumin. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of serum CK18-Asp396 levels for assessing disease activity. Results: A higher level of serum CK 18 concentrations was found in patients with significant inflammation vs no significant inflammation (378.5 [interquartile range {IQR}: 173.2-629.6] vs 137.3 [87.5-197.7], P < 0.05; approximately threefold increase) and in patients with significant fibrosis vs no significant fibrosis (177.8 [IQR: 120.8-519.1] vs 142.7 [IQR: 88.8-214.4], P < 0.05; 1.25-fold increase). There was no differential CK 18 level by degree of steatosis. CK 18 was an independent predictor of significant inflammation with an 82% specificity and a 94% negative predictive value. We found the strongest correlation of CK 18 with alanine aminotransferase and aspartate aminotransferase (both r = 0.52; P < 0.001), but less with albumin (r = -0.24; P < 0.05) and viral load (log) (r = 0.19; P < 0.05). Conclusion: CHB appears to be accompanied by continuous high levels of hepatocyte apoptosis as judged from serum CK 18, suggesting that elimination of the infected compartment constitutes a defensive strategy against disease. Accordingly, CK 18 works as an independent predictor of significant inflammation with a high specificity

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were prepared from brain cortex, hippocampus and striatum. Hepatic encephalopathy was induced by a two-stage liver devascularization procedure and acute hyperammonemia by a prolonged ammonium-acetate infusion; rabbits receiving a sodium-potassium-acetate infusion served as controls. In these animal models extracellular brain glutamate levels are known to be elevated. However no significant alterations in the number nor the affinity of the MK-801 binding sites of the NMDA receptors were found during acute liver failure and acute hyperammonemia. These findings suggest that the NMDA receptor population remains unaltered in experimental encephalopathy from acute liver failure and acute hyperammonemia, desp

Liver stiffness is associated with excess mortality in the general population driven by heart failure:The Rotterdam Study

Background: Elevated liver stiffness reflects hepatic fibrosis but can also be secondary to venous congestion. We aimed to study the association between liver stiffness and mortality in the general population, stratified for heart failure and/or coronary heart disease (CHD). Methods: We analysed individuals enrolled in the ongoing prospective population-based Rotterdam Study who attended a visit between 2009–2014 that included liver stiffness measurement. Exclusion criteria for the primary analysis were incomplete data on heart failure, unreliable liver stiffness, alcohol abuse and viral hepatitis, leaving 4.153 participants (aged 67.5 ± 8.4 years, 44.2% male) for analysis with a median follow-up of 6.0 (interquartile range: 5.1–7.0) years. Secondary analysis included participants with viral hepatitis, alcohol abuse and/or unreliable measurement. The association between liver stiffness and mortality was assessed using Cox regression. Associations between heart failure, CHD, and echocardiographic characteristics and liver stiffness were quantified with linear regression. Results: Liver stiffness ≥8.0 kPa was associated with mortality (aHR: 1.37, 95%CI: 1.00–1.89). However, this was driven by participants with heart failure (aHR: 2.48, 95%CI: 1.15–5.35), since high liver stiffness was not associated with mortality in participants without heart failure and/or CHD (aHR: 1.07, 95%CI: 0.70–1.64). Results were consistent when individuals with viral hepatitis, alcohol abuse or unreliable liver stiffness measurement were not excluded. Several cardiovascular characteristics were significantly associated with higher liver stiffness, e.g. heart failure, moderate/poor diastolic dysfunction, and right atrium diameter &gt; 4.5 cm. Conclusion: In our cohort of community-dwelling elderly, high liver stiffness was associated with excess mortality, primarily explained by participants with heart failure. Moreover, heart failure and its indicators were associated with increased liver stiffness.</p

Tamoxifen use and potential effects on liver parenchyma:A long-term prospective transient elastographic evaluation

Tamoxifen is a commonly prescribed drug in both early and metastatic breast cancer. Prospective studies in Asian populations demonstrated that tamoxifen‐related liver steatosis occurred in more than 30% of the patients within 2 years after start of treatment. No well‐designed prospective studies on potential tamoxifen‐related liver steatosis have been conducted in Caucasian patients so far. Therefore, our prospective study aimed to assess the incidence of tamoxifen‐related liver steatosis for a period of 2 years in a population of Caucasian breast cancer patients treated with tamoxifen. Patients with an indication for adjuvant treatment with tamoxifen were included in this study. Data were collected at 3 months (T1) and at 2 years (T2) after start of tamoxifen treatment (follow‐up period of 21 months). For the quantification of liver steatosis, patients underwent liver stiffness measurement by transient elastography with simultaneous controlled attenuation parameter (CAP) determination using the FibroScan. A total of 95 Caucasian breast cancer patients were included in this evaluation. Liver steatosis was observed in 46 of 95 (48%) and 48 of 95 (51%) of the patients at T1 and T2, respectively. No clinically relevant increase in liver steatosis was observed during the treatment period of 2 years with tamoxifen (median CAP = 243 ± 49 dB/m (T1) and 253 ± 55 dB/m (T2), respectively; p = 0.038). Conclusion: In this prospective longitudinal study in Caucasian breast cancer patients, no clinically relevant alterations in liver steatosis in terms of CAP values and liver/lipid parameters were observed after 2 years of tamoxifen treatment. This study therefore demonstrates an absence of tamoxifen‐related adverse events such as steatosis and (early) development of fibrosis or cirrhosis during a treatment period of at least 2 years