Development and validation of ultra-performance liquid chromatography-tandem mass spectrometric methods for simultaneous and rapid determination of contezolid and its major metabolite M2 in plasma and urine samples and its application to a study in subjects with moderate liver impairment.

Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment.

Untargeted metabolomic profiling of urine from healthy dogs and dogs with chronic hepatic disease.

Chronic hepatic disease can present a diagnostic challenge with different etiologies being associated with similar clinical and laboratory findings. The histopathological assessment of a liver biopsy specimen is usually required in order to make a definitive diagnosis and the availability of non-invasive prognostic biomarkers is limited. The emerging science of metabolomics is used to detect changes in endogenous low molecular weight metabolites in biological samples and offers the possibility of identifying noninvasive markers of disease. The objective of this study was to investigate differences in the urine metabolome between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Stored urine samples from 10 healthy dogs, 10 dogs with chronic hepatitis, 6 dogs with hepatocellular carcinoma, and 5 dogs with a congenital portosystemic shunt were analyzed. The urine metabolome was analyzed by gas chromatography-quadrupole time of flight mass spectrometry and 220 known metabolites were identified. Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering between groups. Random forest analysis showed differences in the abundance of various metabolites including putrescine, gluconic acid, sorbitol, and valine. Based on univariate statistics, 37 metabolites were significantly different between groups. In, conclusion, the urine metabolome varies between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Further targeted assessment of these metabolites is needed to assess their diagnostic utility.

Increased oxidative damage of RNA in liver injury caused by hepatitis B virus (HBV) infection.

To evaluate the urinary levels of 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in liver injury patients with hepatitis B virus (HBV) infection and to explore the relationship between urinary 8-oxo-dGsn or 8-oxo-Gsn and degree of liver damage. We enrolled 138 liver injury patients with HBV infection and 169 age- and sex-matched healthy controls in this study. A sensitive and accurate isotope-diluted liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) method was used to measure the urinary levels of 8-oxo-Gsn and 8-oxo-dGsn. Simultaneously, pathological analysis of liver biopsy tissues was carried out, and immunohistochemistry was carried out for 8-oxo-Guo, 8-oxo-dGuo and MTH1 protein in some liver injury tissues. We analysed the correlation between the degrees of inflammation and fibrosis and levels of 8-oxo-Gsn and 8-oxo-dGsn. We also analysed the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn with clinical data of HBeAg, HBsAg, and HBV genotype and detected the levels of plasma aspartate aminotransferase, alanine aminotransferase (AST), platelet, alkaline phosphatase, prothrombin time (PT) and HBV DNA, and calculated the aspartate amino transferase-to-platelet ratio index (APRI) score. Nonparametric correlations were used to evaluate the correlation between 8-oxo-Gsn, 8-oxo-dGsn or APRI and various laboratory biochemical indicators. Results showed that the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn in patients with liver injury were significantly higher than those of healthy controls (both p < .001). Urinary 8-oxo-Gsn was significantly associated with AST, APRI and PT (p = .013, p = .026 and p = .049). The receiver operating characteristic curves of 8-oxo-Gsn were 0.696 (0.632-0.759) and 0.731 (0.672-0.790) for inflammatory activity and fibrosis, respectively. Patients with higher levels of urinary 8-oxo-Gsn are more likely to have a high degree of fibrosis and urinary 8-oxo-Gsn may have a great potential in assessing liver fibrosis.

El análisis de orina como herramienta diagnóstica en casos de malaria grave / Urinalysis as a diagnostic tool in severe malaria

Resumen La malaria produce complicaciones y muerte especialmente en poblaciones con acceso limitado a la atención en salud. La malaria grave puede reconocerse tempranamente mediante la detección en la orina de hallazgos como la hematuria, la coluria y la proteinuria. Se hizo una revisión narrativa basada en estudios sobre malaria grave y el empleo del análisis de orina mediante la consulta de 91 publicaciones. Mediante el análisis de la orina, se pueden detectar alteraciones metabólicas y lesiones en distintos órganos. En estudios recientes en Colombia se ha confirmado su utilidad como apoyo en el diagnóstico de la disfunción renal, la disfunción hepática y la anemia asociada con hemólisis, las cuales son complicaciones frecuentes en la malaria. El examen constituye una herramienta de fácil aplicación en la consulta ambulatoria y en pacientes hospitalizados para reconocer tempranamente casos complicados, y permite la detección oportuna de diferentes lesiones en el paciente con malaria, contribuyendo así a la reducción de la morbilidad grave y la mortalidad.

Abstract Malaria accounts for a significant morbidity and mortality rate around the world, especially in communities with limited access to healthcare. Some clinical signs in urine, like haematuria, coluria and proteinuria, help for the early diagnosis of severe malaria cases. A narrative review was conducted by analyzing 91 publications on studies about severe malaria cases and the use of urinalysis. A urinalysis can detect metabolic disturbances and organ injury. Its diagnostic utility for frequent complications caused by malaria, such as hepatic injury, kidney dysfunction and hemolysis, has been confirmed by recent Colombian studies. This test is an easy-to-use tool in outpatient clinics and with hospitalized patients to promptly recognize complicated cases, allowing the timely identification of different lesions in patients with malaria, thus contributing to the reduction of severe morbidity and mortality.

Characterization of aminoaciduria and hypoaminoacidemia in dogs with hepatocutaneous syndrome.

OBJECTIVE To characterize aminoaciduria and plasma amino acid concentrations in dogs with hepatocutaneous syndrome (HCS). ANIMALS 20 client-owned dogs of various breeds and ages. PROCEDURES HCS was definitively diagnosed on the basis of liver biopsy specimens (n = 12), gross and histologic appearance of skin lesions (4), and examination of skin and liver biopsy specimens (2) and presumptively diagnosed on the basis of cutaneous lesions with compatible clinicopathologic and hepatic ultrasonographic (honeycomb or Swiss cheese pattern) findings (2). Amino acid concentrations in heparinized plasma and urine (samples obtained within 8 hours of each other) were measured by use of ion exchange chromatography. Urine creatinine concentration was used to normalize urine amino acid concentrations. Plasma amino acid values were compared relative to mean reference values; urine-corrected amino acid values were compared relative to maximal reference values. RESULTS All dogs had generalized hypoaminoacidemia, with numerous amino acid concentrations < 50% of mean reference values. The most consistent and severe abnormalities involved glutamine, proline, cysteine, and hydroxyproline, and all dogs had marked lysinuria. Urine amino acids exceeding maximum reference values (value > 1.0) included lysine, 1-methylhistidine, and proline. CONCLUSIONS AND CLINICAL RELEVANCE Hypoaminoacidemia in dogs with HCS prominently involved amino acids associated with the urea cycle and synthesis of glutathione and collagen. Marked lysinuria and prolinuria implicated dysfunction of specific amino acid transporters and wasting of amino acids essential for collagen synthesis. These findings may provide a means for tailoring nutritional support and for facilitating HCS diagnosis.

Blood mercury concentrations are associated with decline in liver function in an elderly population: a panel study.

BACKGROUND: Mercury is a toxic heavy metal and is known to affect many diseases. However, few studies have examined the effects of mercury exposure on liver function in the general population. We examined the association between blood mercury concentrations and liver enzyme levels in the elderly. METHODS: We included 560 elderly participants (60 years or older) who were recruited from 2008 to 2010 and followed up to 2014. Subjects visited a community welfare center and underwent a medical examination and measurement of mercury levels up to five times. Analyses using generalized estimating equations model were performed after adjusting for age, sex, education, overweight, alcohol consumption, smoking, regular exercise, high-density lipoproteins cholesterol, and total calorie intake. Additionally, we estimated interaction effects of alcohol consumption with mercury and mediation effect of oxidative stress in the relationship between mercury levels and liver function. RESULTS: The geometric mean (95% confidence interval (CI)) of blood mercury concentrations was 2.81 µg/L (2.73, 2.89). Significant relationships were observed between blood mercury concentrations and the level of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT), after adjusting for potential confounders (P < 0.05). The odds ratios of having abnormal ALT levels were statistically significant in the highest mercury quartile compared to those with the lowest quartile. Particularly, regular alcohol drinkers showed greater effect estimates of mercury on the liver function than non-drinkers groups. There was no mediation effect of oxidative stress in the relationship between blood mercury concentrations and liver function. CONCLUSIONS: Our results suggest that blood mercury levels are associated with elevated liver enzymes and interact with alcohol consumption for the association in the elderly.

Urine albumin-to-creatinine ratio is associated with the severity of liver disease, renal function and survival in patients with decompensated cirrhosis.

BACKGROUND AND AIMS: To investigate if urine albumin-to-creatinine ratio (UACR) is associated with the presence of glomerular filtration rate (GFR) <60 mL/min, severity of liver disease and survival in patients with stable decompensated cirrhosis. METHODS: We evaluated prospectively 220 patients (73 % male, age 52.8 ± 12 years). In each patient, assessment of GFR was based on 51chromium-EDTA. Random urine samples were obtained for measurement of UACR. RESULTS: Thirty-eight patients (17 %, group 1) had UACR ≥30 mg/g and 182 (83 %, group 2) had UACR <30 mg/g. Group 1, compared to group 2 patients, had significantly lower levels of "true" GFR (61 vs. 71 ml/min, p = 0.035). Patients with "true" GFR <60 mL/min (n = 93), compared to those with "true" GFR ≥60 mL/min (n = 127), had higher levels of UACR (16 vs. 11.3 mg/g, p = 0.023). In multivariate analysis, serum creatinine and UACR (ΟR 0.98, 95 % CI 0.95-0.99, p = 0.04) were independently associated with the presence of GFR <60 mL/min. Based on the area under the ROC curves, the best cut-off point for UACR was >16.51 mg/g giving a sensitivity 70 %, specificity 49 %, PPV 68 % and NPV 51 %. During the follow-up period [17 (6-52) months], the patients who died or underwent LT (n = 158), compared to those who remained alive (n = 62), had higher levels of UACR (41 vs. 13 mg/g, p = 0.025). Patients with UACR ≥30 mg/g had worse outcome, compared to those with UACR <30 mg/g (log rank p = 0.053). CONCLUSIONS: We showed for the first time that UACR ≥30 mg/g was associated with more severe liver disease, lower GFR and worse LT-free survival in patients with decompensated cirrhosis. However, further studies are needed to confirm these findings.

Association between Aflatoxin M1 and Liver Disease in HBV/HCV Infected Persons in Ghana.

Aflatoxins are produced by the fungi Aspergillus flavus and Aspergillus parasiticus and are common food contaminants in tropical developing countries. Extensive aflatoxin consumption has been shown to be highly associated with liver disease. A case-control study was conducted to determine the association between aflatoxin and liver disease in Kumasi, Ghana. A questionnaire was administered to examine socio-demographic characteristics and food storage and consumption practices, and urine samples were collected to measure levels of the aflatoxin metabolite (AFM1). Two hundred and seventy-six people participated in the study; 38 had liver disease (cases), 136 had neither hepatitis B/C nor liver disease (negative controls), and 102 were hepatitis B/C positive without liver cancer (positive controls). A much higher percent of participants in each group was male (76% of cases, 88% of negative controls and 65% of positive controls). Multivariate analysis showed that age was a significant predictor for being a case when cases were compared to negative controls. The odds of being a case was 70% less for participants aged 25-34 years (odds ratios (OR) 0.30; 95% confidence interval (CI) 0.10-0.88) compared to those ≥45 years. For cases; Akans were seven times more likely to have AFM1 levels below the median when compared to other ethnic groups (OR 7; CI 1.41-34.68). When cases were compared to positive controls, they were 2.29 times more likely to report awareness of aflatoxin contamination of groundnuts (95% CI 1.06-4.91). Cases were also two times more likely to report awareness of aflatoxin contamination of maize than all controls combined (95% CI 1.02-4.11). However, most cases reported that aflatoxin contamination does not cause sickness in humans. This shows that there is awareness of aflatoxin contamination without proper understanding of the serious potential adverse health impacts among these study participants. These findings indicate that educational interventions that stress the harmful health effects of aflatoxin in food, with an emphasis on the higher risk for males, are urgently needed. The reasons for lower aflatoxin levels among Akans need to be determined, and the findings used to design interventions that benefit other ethnic groups in the society.

People with diabetes, respiratory, liver or mental disorders, higher urinary antimony, bisphenol A, or pesticides had higher food insecurity: USA NHANES, 2005-2006.

This study was aimed to examine the prevalence of food insecurity and what social, health, and environmental characteristics could constitute such situation in a national and population-based setting. Data was retrieved from the National Health and Nutrition Examination Survey, 2005-2006. Information on demographics, lifestyle factors, self-reported ever medical conditions in the past and self-reported food security conditions in the last 12 months calculated on the household level was obtained by household interview. Bloods and urines (subsample) were collected at the interview as well. Only adults aged 20 years and above (n = 4979) were included for statistical analysis in the present study. Chi-square test, t test, and survey-weighted logistic regression modeling were performed. Three thousand eight hundred thirty-four (77.9%) people were with full food security, 466 (9.5%) people were with marginal food security and 624 (12.7%) people were with low or very low food security. Being younger, having higher ratios of family income to poverty thresholds (due to low level of education or lack of financial support), having prior asthma, arthritis, chronic bronchitis, depression, diabetes, eczema, emphysema or liver problems, having higher levels of serum cotinine, urinary antimony, bisphenol A, pesticides, or having lower levels of urinary Benzophenone-3 were associated with food insecurity. In addition to socioeconomic and smoking conditions, evidence on people with several prior health conditions and being exposed to environmental chemicals and food insecurity is further provided. Future social, health and environmental policy, and programs protecting people from food insecurity by considering both health and environmental factors mentioned above would be suggested.

Health risks associated with crude oil spill exposure.

BACKGROUND: Human exposure to crude oil spills is associated with multiple adverse health effects including hematopoietic, hepatic, renal, and pulmonary abnormalities. The purpose of this study was to assess the hematological and liver function indices among the subjects participating in the Gulf oil spill cleanup operations in comparison with the standardized normal range reference values. METHODS: Using medical charts, clinical data (including white blood cell [WBC] count, platelet count, hemoglobin, hematocrit, blood urea nitrogen [BUN] creatinine, alkaline phosphatase [ALP], aspartate amino transferase [AST], alanine amino transferase [ALT], and urinary phenol) were gathered for the subjects who were exposed to the Gulf oil spill and analyzed. RESULTS: A total of 117 subjects exposed to the oil spill were included. Over 77% of subjects had WBC counts in the mid range (6-10 × 10(3) per µL), while none of the subjects had the upper limit of the normal range (11 × 10(3) per µL). A similar pattern was seen in the platelet counts and BUN levels among the oil spill-exposed subjects. Conversely, over 70% of the subjects had creatinine levels toward the upper limit of the normal range and 23% of subjects had creatinine levels above the upper limit of the normal range (>1.3 mg per dL). Similarly, hemoglobin and hematocrit levels were toward the upper limit of normal in more than two thirds of the subjects. AST and ALT levels above the upper limit of normal range (>40 IU per L) were seen in 15% and 31% of subjects, respectively. Over 80% of subjects had urinary phenol levels higher than detectable levels (2 mg per L). CONCLUSION: The results of this study support our earlier study findings in which we found that people who participated in oil spill cleanup activities are at risk of developing alterations in hematological profile and liver function.

Investigation of delta-aminolevulinic acid dehydratase polymorphism affecting hematopoietic, hepatic and renal toxicity from lead in Han subjects of southwestern China.

UNLABELLED: This study is to explore the effect of ALAD polymorphism on hematopoietic, hepatic and renal toxicity from lead in occupational exposure workers. METHODS: We conducted a cross-sectional study on 156 workers with occupational exposure to lead between 2002 and 2007. The results of laboratory examinations were analyzed. RESULTS: The authors found that workers with the ALAD 1-1 genotype were associated with higher blood lead level than those with the ALADl-2 genotype. Blood and urine lead levels were much higher in storage battery workers than in cable workers. The urine ALA and blood ZPP levels in workers with the ALAD 1-1 genotype were higher than those with the ALADl-2 genotype. The serum Cr level in workers with the ALADl-1 genotype was much higher than those with the ALADl-2 genotype especially in higher lead exposure level. CONCLUSIONS: The ALAD-2 protein might modify the kinetics of lead in blood at a relatively higher blood lead level and protect against hematopoietic, hepatic and renal toxicity from lead. Urine ALA, blood ZPP and serum Cr levels might be considered as effective biological monitoring partners of lead induced hematopoietic and renal toxicology.

Is it necessary to re-evaluate diagnostic criteria for Wilson disease in children?

BACKGROUND/AIMS: The differential diagnosis of Wilson Disease (WD) is challenging, especially in children, because liver copper levels may also increase in other chronic liver diseases with bile stasis. The aim of this study is to determine urine and liver copper cut-off values to differentiate WD from other chronic liver diseases (non-WD, NWD) in children. MATERIALS AND METHODS: Seventy-six patients participated in the study, 35 with WD and 41 with NWD. The two groups were divided into two subgroups according to the presence of cholestasis. At the time of diagnosis, age, sex, biochemical test results, serum ceruloplasmin, baseline 24-h urinary copper levels, liver biopsy histological findings, liver copper levels, and Child-Pugh scores were obtained from medical records. Copper content in liver tissue and copper levels in urine were measured by atomic absorption spectrometry. Cut-off values for differentiation of WD from NWD were determined by receiver operating characteristic (ROC) analysis. RESULTS: A liver copper cut-off value of 98 µg/g indicated WD with 91% sensitivity and 65.4% specificity (area under the curve =0.838, 95% CI: 0.749-0.927). A 24-h urinary copper cut-off value of 67.5 µg/24h indicated WD with 85% sensitivity and 71% specificity (area under the curve =0.843, 95% CI: 0.752-0.934). CONCLUSION: In this study of pediatric chronic liver disease patients, copper cut-off values for distinguishing WD differed substantially from those used for diagnosis. A larger scale study is warranted to re-evaluate liver copper and 24-h urinary copper cut-offs for children with suspected WD.

Urinary excretion of copper, zinc and iron with and without D-penicillamine administration in relation to hepatic copper concentration in dogs.

Hereditary copper-associated hepatitis in dogs resembles Wilson's disease, a copper storage disease in humans. Values for urinary copper excretion are well established in the diagnostic protocol of Wilson's disease, whereas in dogs these have not been evaluated. The objectives of this study were to characterize both basal and D-penicillamine induced urinary copper, zinc and iron excretion in dogs in relation to hepatic copper concentration. Beagles, Beagle-Bedlington terrier cross-breeds homozygous for the COMMD1 gene mutation that causes copper toxicosis, and Labrador retrievers with normal or increased hepatic copper concentrations were investigated. The hepatic copper phenotype was determined by histological evaluation of liver biopsies and measurement of the hepatic copper concentration by instrumental neutron activation analysis. Urinary excretion of copper, iron and zinc was measured via inductively coupled plasma optical emission spectrometry under basal conditions and after oral administration of a single dose (20mg/kg bodyweight) of the chelator D-penicillamine. There was a rapid increase in urinary excretion of copper and zinc, but not iron after D-penicillamine administration. This increase was not different between dogs with high or normal hepatic copper concentrations. D-penicillamine-induced urinary copper excretion and the copper/creatinine ratio did not correlate with hepatic copper concentrations in the dogs studied, although basal urinary copper/zinc ratios did correlate with hepatic copper concentrations in Labrador retrievers. The latter parameter may be useful in diagnostic and follow-up protocols for copper-associated hepatitis in Labrador retrievers.

Exploratory urinary metabolic biomarkers and pathways using UPLC-Q-TOF-HDMS coupled with pattern recognition approach.

Metabolomics represents an emerging and powerful discipline concerned with the comprehensive analysis of small molecules and provides a powerful approach to discover biomarkers in biological systems. Recent development of biomarkers for diagnosis and therapeutic monitoring of liver-stagnation and spleen-deficiency syndrome (LSS)-type disease remains challenging. This study was undertaken to discover novel potential biomarkers for the non-invasive early diagnosis of human LSS. Urine samples which are potentially a rich source of metabolites were collected from patients with LSS, together with healthy control samples. Metabolite profiling was performed by ultra-performance liquid-chromatography/electrospray-ionization synapt high-definition mass spectrometry (UPLC-Q-TOF-HDMS) in conjunction with multivariate data analysis and ingenuity pathway analysis that were used to select the metabolites to be used for the non-invasive diagnosis of LSS. Twelve urinary differential metabolites contributing to the complete separation of LSS patients from matched healthy controls were identified involving several key metabolic pathways such as pentose and glucuronate interconversions, ascorbate, aldarate, cysteine, methionine, tyrosine, tryptophan, amino sugar and nucleotide sugar metabolism. More importantly, of the 12 differential metabolites, 4 metabolite markers, prolylhydroxyproline, L-homocystine, 2-octenoylcarnitine and α-N-phenylacetyl-L-glutamine, were effective for the diagnosis of human LSS, with an achieved sensitivity of 93.0%. These results demonstrate that robust metabolomics has the potential as a non-invasive strategy and promising screening tool to evaluate the potential of these metabolites in the early diagnosis of LSS patients and provides new insight into pathophysiological mechanisms.

Cytokine elevation and transaminitis after laparoscopic donor nephrectomy.

Acute kidney injury frequently occurs in the critically ill and often progresses into multiorgan dysfunction syndrome, resulting in high mortality. We previously showed that nephrectomized mice had increased interleukin (IL)-6 and tumor necrosis factor (TNF)-α that directly contributed to systemic inflammation and hepatic injury. In this study, we examined whether patients undergoing laparoscopic donor nephrectomy have increased postoperative cytokine levels with injury to the liver and whether the remaining kidney sustains injury. Serial serum and urine samples were collected from 32 patients undergoing laparoscopic donor nephrectomy and 17 patients undergoing nonrenal laparoscopic surgery. Serum IL-6, IL-18, TNF-α and monocyte chemotactic protein-1 (MCP-1) (markers of systemic inflammation) and urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), MCP-1, and IL-18 (markers of acute kidney injury) were quantified by enzyme-linked immunosorbent assay. We also analyzed serum creatinine, aspartate transaminase (AST), and alanine transaminase to assess liver injury. Patients who underwent donor nephrectomy not only demonstrated increased serum creatinine but also had significant increases in serum IL-6, MCP-1, and AST. Serum TNF-α also trended upward in donor nephrectomy patients. Finally, the donor nephrectomy group showed increased urinary NGAL but not KIM-1 at 24 h. Taken together, our findings of increased serum IL-6, MCP-1, and AST after donor nephrectomy suggest that an acute reduction of kidney function induces systemic inflammation and may have distant effects on the liver. Further studies are needed to correlate increased urinary NGAL after donor nephrectomy both as a potential marker for renal tubular stress and/or hypertrophy in the contralateral kidney.

[High levels of sterigmatocystin in patients with chronic liver diseases]. / Detectarea sterigmatocistinei la pacientii cu boala ii hepatica cronica.

UNLABELLED: Sterigmatocystin (STC) is a wide spread mycotoxin produced by Aspergillus fungi, with hepatotoxic and carcinogenetic proprieties. OBJECTIVES: To determine the STC concentration in blood and urine from patient with liver cirrhosis (LC) and hepatocellular carcinoma (HCC), with correlation with liver function parameters. MATERIAL AND METHODS: The study enrolled 166 patients divided in three groups: control--55 patients (27M, 28F); LC--58 patients (31M, 27F); HCC--53 patients (26M, 27F). 20 ml of blood and 50 ml of urine were collected from each patient and liver enzymes and alfa-fetoprotein (AFP) were measured. STC was determined by high performance liquid chromatography, with concomitant detection in ultraviolet and fluorescence. RESULTS: STC was detected in 26.2% of samples, more frequently in LC and HCC groups (p < 0.001). STC mean values were 0.014 ng/ml and 0.005 ng/ml in blood, respective urine of controls, rising to 0.626 ng/ml (p = 0.003) respective 1.053 ng/ml (p = 0.049) in LC and 2.02 ng/ml in blood (p < 0.0001) and 9.39 ng/ml in urine (p = 0.003) in patients with HCC. There is a perfect correlation between serum and urinary levels of STC in controls (r = 1), that become weak in patients with LC (r = 0.48) and insignificant in HCC (r = 0.15). AFP values were significantly correlated with STC concentration in patient with HCC, in both blood (r = 0.31) and urine (r = 0.84). CONCLUSIONS: STC values in patients with LC and HCC were significantly higher compared to controls. Strong positive correlation of STC with AFP in patients with liver cancer suggested a possible role of this mycotoxin in pathogenesis of the disease.

Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies.

BACKGROUND: Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure. METHODS: Open-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age. RESULTS: In the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups. CONCLUSIONS: Zibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).

Clinical significance of measuring urinary sulfated bile acids in adult patients with hepatobiliary diseases.

BACKGROUND/AIMS: Measurement of urinary sulfated bile acid (USBA) level is a simple urine test that reflects the degree of cholestasis in newborns. The aim of this study was to clarify the clinical significances of this test for liver diseases in adults. METHODOLOGY: We examined the relationship between USBA level in a urine sample by enzymatic assay and clinical parameters and postoperative complications in 27 patients with hepatobiliary diseases who underwent surgical procedures between 2002 and 2007. RESULTS: Mean USBA in all patients before surgery was 39.8 +/- 64.0 micromol/L (median value was 6.6). USBA level was increased in patients with cholestasis. USBA level was significantly correlated with serum total bile acid, total bilirubin level and serum hyaluronic acid level (r = 0.850, 0.602 and 0.504, respectively) (p < 0.05) and, furthermore, tended to be correlated with liver-uptake ratio (LHL15) by technetium-99m galactosyl human serum albumin (99SmTc-GSA) scintigraphy and alanine aminotransferase level (r = -0.469 and 0.436, respectively but not significant). USBA level tended to be associated with postoperative uncontrolled ascites (p = 0.050, not significant). Postoperative USBA level by day 7 was not changed; however, USBA level in patients with cholestatic diseases was decreased. CONCLUSIONS: USBA is a simple and sensitive noninvasive test for cholestasis and also useful to predict postoperative uncontrolled ascites after hepatic resections.

Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults.

CONTEXT: Bisphenol A (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans. OBJECTIVE: To examine associations between urinary BPA concentrations and adult health status. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of P < .05. MAIN OUTCOME MEASURES: Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes. RESULTS: Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P = .001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P < .001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes gamma-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P < .001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P = .002). CONCLUSION: Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.

Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload.

BACKGROUND/AIMS: Many patients with hepatic iron overload do not have identifiable mutations and often present with metabolic disorders and hepatic steatosis. Since the pathophysiology of Dysmetabolic Hepatic Iron Overload (DHIO) is still obscure, the aim of this study was to evaluate, in these patients, possible alterations in iron-related molecule expression. METHODS: Iron-related gene mRNA levels were determined by quantitative-PCR in liver biopsies of subjects with NAFLD without iron overload and patients with HFE-hemochromatosis, beta-thalassemia major and DHIO. Urinary hepcidin was measured by immunoblotting. RESULTS: No alterations in mRNA expression of either iron transporters or exporters were found in DHIO. mRNA and urinary hepcidin levels normalized for the amount of iron overload showed a significantly lower ratio than in controls, although not as low as in hemochromatosis or beta-thalassemia. Differently from what observed in hemochromatosis, hepcidin mRNA did not correlate with urinary hepcidin. CONCLUSIONS: Patients with DHIO show appropriate regulation of mRNAs encoding proteins involved in iron uptake and efflux but dysregulation of hepcidin production. The relatively elevated urinary hepcidin can explain the iron phenotype in DHIO (more macrophage iron retention and low/normal transferrin saturation).