In Silico Identification of Chemicals Capable of Binding to the Ecdysone Receptor.

The process of molting, known alternatively as ecdysis, is a feature integral in the life cycles of species across the arthropod phylum. Regulation occurs as a function of the interaction of ecdysteroid hormones with the arthropod nuclear ecdysone receptor-a process preceding the triggering of a series of downstream events constituting an endocrine signaling pathway highly conserved throughout environmentally prevalent insect, crustacean, and myriapod organisms. Inappropriate ecdysone receptor binding and activation forms the essential molecular initiating event within possible adverse outcome pathways relating abnormal molting to mortality in arthropods. Definition of the characteristics of chemicals liable to stimulate such activity has the potential to be of great utility in mitigation of hazards posed toward vulnerable species. Thus the aim of the present study was to develop a series of rule-sets, derived from the key structural and physicochemical features associated with identified ecdysone receptor ligands, enabling construction of Konstanz Information Miner (KNIME) workflows permitting the flagging of compounds predisposed to binding at the site. Data describing the activities of 555 distinct chemicals were recovered from a variety of assays across 10 insect species, allowing for formulation of KNIME screens for potential binding activity at the molecular initiating event and adverse outcome level of biological organization. Environ Toxicol Chem 2020;39:1438-1450. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells.

Metamizole is an analgesic and antipyretic, but can cause neutropenia and agranulocytosis. We investigated the toxicity of the metabolites N-methyl-4-aminoantipyrine (MAA), 4-aminoantipyrine (AA), N-formyl-4-aminoantipyrine (FAA) and N-acetyl-4-aminoantipyrine (AAA) on neutrophil granulocytes and on HL60 cells (granulocyte precursor cell line). MAA, FAA, AA, and AAA (up to 100 µM) alone were not toxic for HL60 cells or granulocytes. In the presence of the myeloperoxidase substrate H2O2, MAA reduced cytotoxicity for HL60 cells at low concentrations (<50 µM), but increased cytotoxicity at 100 µM H2O2. Neutrophil granulocytes were resistant to H2O2 and MAA. Fe2+ and Fe3+ were not toxic to HL60 cells, irrespective of the presence of H2O2 and MAA. Similarly, MAA did not increase the toxicity of lactoferrin, hemoglobin or methemoglobin for HL60 cells. Hemin (hemoglobin degradation product containing a porphyrin ring and Fe3+) was toxic on HL60 cells and cytotoxicity was increased by MAA. EDTA, N-acetylcystein and glutathione prevented the toxicity of hemin and hemin/MAA. The absorption spectrum of hemin changed concentration-dependently after addition of MAA, suggesting an interaction between Fe3+ and MAA. NMR revealed the formation of a stable MAA reaction product with a reaction pathway involving the formation of an electrophilic intermediate. In conclusion, MAA, the principle metabolite of metamizole, increased cytotoxicity of hemin by a reaction involving the formation of an electrophilic metabolite. Accordingly, cytotoxicity of MAA/hemin could be prevented by the iron chelator EDTA and by the electron donors NAC and glutathione. Situations with increased production of hemin may represent a risk factor for metamizole-associated granulocytopenia.

Prognostic Value of Metabolic Liver Function Tests: a Study on 711 Cirrhotic Patients.

BACKGROUND AND AIMS: The prognosis of cirrhotic patients is usually assessed by Child-Pugh and MELD scores. Metabolic liver function tests such as aminopyrine breath test (ABT) and indocyanine green clearance (IGC) have been shown to reveal hepatocellular dysfunction. The aim of this retrospective study was to compare the prognostic value of the MELD score, Child-Pugh score, ABT and IGC in a large cohort of cirrhotic patients. METHODS: Between January 1996 and June 2008, 711 cirrhotic patients were included and the primary endpoint was survival without LT. The ROC curves with c-statistics, correlation coefficient and survival were calculated. RESULTS: Metabolic function tests and scores were strongly correlated. At the time of evaluation, 111 patients had died and 520 had received a transplant. Prognostic ability (estimated by the AUROC curve) to predict survival without LT at 6 months was 0.662, 0.691, 0.738 and 0.715 for ABT, IGC, Child-Pugh score and MELD score, respectively. Similarly, at 1 year, AUROC was 0.738 for Child-Pugh score, 0.716 for MELD score, 0.693 for IGC clearance and 0.651 for ABT. CONCLUSIONS: Our results strongly confirm that IGC and ABT have a high prognostic value in cirrhotic patients, similar to Child-Pugh and MELD scores. They could be developed to routinely evaluate the prognosis of patients in addition to clinical and biochemical data.

Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of in vitro diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the in vitro diagnosis of allergic reactions to metamizole.

Simultaneous determination of aminopyrine and antipyrine in porcine muscle, milk, and eggs using liquid chromatography with tandem mass spectrometry.

The concentrations of residual aminopyrine and antipyrine in porcine muscle, milk, and egg samples were analyzed using liquid chromatography with tandem mass spectrometry after undergoing a series of sample pretreatment steps. Owing to an ion suppression effect, matrix-matched calibrations were used for analyte quantitation with determination coefficients (R(2) ) ≥ 0.9931. The recovery rates for aminopyrine and antipyrine in various matrices at two spiking levels (5 and 10 ng/g) fell in the range of 60.96-68.87 and 61.87-66.99%, respectively. Meanwhile, the intra- and inter-day precisions (expressed as relative standard deviation) were 1.02-12.95 and 1.71-5.50%, respectively. The method's detection limit (1 ng/g) was very low, thus enabling the detection of low residue levels. The applicability of the developed method was demonstrated with actual market samples and none of the tested analytes was detected in any of the samples.

Curiosities in drug metabolism.

1. It is inevitable that during some xenobiotic biotransformation studies, a certain metabolite or degradation product arises of which the identity is uncertain, the route of formation is ambiguous, or it is just a plain mystery. 2. The following communication draws attention to three drugs reported in the literature, chlorphentermine, phenothiazine and aminopyrine, where after many years of investigation there still exists uncertainty over some of their metabolites. Noticeably, these three examples probably involve (potential) interaction of a nitrogen centre within the drug molecule. 3. It is hoped that the resurrection and assemblage of these data will offer interesting reading and that these examples may prove sufficiently intriguing to motivate further exploration and some resolution of these lingering concerns.

Critical appraisal of 13C breath tests for microsomal liver function: aminopyrine revisited.

As liver diseases are a major health problem and especially the incidence of metabolic liver diseases like non-alcoholic fatty liver disease (NAFLD) is rising, the demand for non-invasive tests is growing to replace liver biopsy. Non-invasive tests such as carbon-labelled breath tests can provide a valuable contribution to the evaluation of metabolic liver function. This review aims to critically appraise the value of the (13) C-labelled microsomal breath tests for the evaluation of metabolic liver function, and to discuss the role of cytochrome P450 enzymes in the metabolism of the different probe drugs, especially of aminopyrine. Although a number of different probe drugs have been used in breath tests, the perfect drug to assess the functional metabolic capacity of the liver has not been found. Data suggest that both the (13) C(2) -aminopyrine and the (13) C-methacetin breath test can play a role in assessing the capacity of the microsomal liver function and may be useful in the follow-up of patients with chronic liver diseases. Furthermore, CYP2C19 seems to be an important enzyme in the N-demethylation of aminopyrine, and polymorphisms in this gene may influence breath test values, which should be kept in mind when performing the (13) C(2) -aminopyrine breath test in clinical practice.

Relationship between 13C-aminopyrine breath test and the MELD score and its long-term prognostic use in patients with cirrhosis.

BACKGROUND: (13)C-Aminopyrine breath test ((13)C-ABT) is a non-invasive, dynamic, quantitative liver function test, and the model for end-stage liver disease (MELD) is a recognised biochemical score used to predict survival in patients with cirrhosis. AIMS: The purpose of this study was to evaluate the relationship between the (13)C-ABT and MELD score in a cohort of cirrhotic patients and, moreover, to assess the prognostic value of (13)C-ABT results in the same group of patients. PATIENTS AND METHODS: Forty-six patients with cirrhosis and without hepatocellular carcinoma who underwent (13)C-ABT and who had at least 1-year follow-up were prospectively included in this study. MELD score was calculated at entry into the study in all patients. End-points of the study were 1-year liver-related death or liver transplantation. RESULTS: (13)C-ABT %dose/h at 30 min (%dose/h30) results showed significant, inverse correlation with MELD scores (r = -0.414, P = 0.004). During 1-year follow-up nine patients died (19.6 %) and two were transplanted (4.3 %). Median (13)C-ABT %dose/h30 results (3.2 vs. 1.8) were significantly higher in patients who survived as compared to those who died or underwent transplantation (P = 0.04). Receiver operating characteristics curves showed that a (13)C-ABT %dose/h30 cut-off of 2.0 had the best accuracy (c-index = 0.717) in assessing 1-year prognosis. CONCLUSIONS: We observed a correlation between a flow-independent quantitative liver function test and the MELD score, and found that the (13)C-ABT may accurately provide long-term prognostic information in cirrhotic patients.

13C-aminopyrine demethylation is decreased in cirrhotic patients with normal biochemical markers.

This study determined the rates of (13)C-aminopyrine metabolism in patients with varying degrees of liver cirrhosis as defined by clinical scores. Twenty-five cirrhotic patients and 18 healthy subjects underwent a (13)C-aminopyrine breath test. The cumulative per cent dose recovery (cPDR) of (13)C on breath expressed as a percentage of the administered dose at 2 h was significantly lower in cirrhotic patients than in healthy subjects (median: 1.7% versus 9.0%; p<.0001). Significant inverse associations between cPDR at 2 h and the model for end-stage liver disease score, Child-Pugh score, international normalised ratio and bilirubin (all p<.05), but not alanine aminotransferase or alkaline phosphatase were observed in the cirrhotic patients. Taking each biochemical marker independently, cirrhotic patients with normal biochemistry had a significantly lower cPDR at 2 h than healthy subjects (all p<.05). Differences in (13)C-aminopyrine metabolism were evident in cirrhotic patients with less severe disease and may mark hepatic dysfunction when conventional biochemical markers appear unchanged.

Influence of different proton pump inhibitors on activity of cytochrome P450 assessed by [(13)C]-aminopyrine breath test.

Aminopyrine is metabolized by cytochrome P450 (CYP) in the liver. The investigators evaluated influences of different PPIs on CYP activity as assessed by the [(13)C]-aminopyrine breath test ([(13)C]-ABT). Subjects were 15 healthy volunteers with different CYP2C19 status (5 rapid metabolizers [RMs], 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]). Breath samples were collected before and every 15 to 30 minutes for 3 hours after oral ingestion of [(13)C]-aminopyrine 100 mg on day 8 of each of the following regimens: control; omeprazole 20 mg and 80 mg, lansoprazole 30 mg, and rabeprazole 20 mg. Changes in carbon isotope ratios in carbon dioxide ((13)CO(2)/(12)CO(2)) in breath samples were measured by infrared spectrometry and expressed as delta-over-baseline (DOB) ratios (‰). Mean areas under the curve of DOB from 0 to 3 h (AUC(0-3h) of DOB) were significantly decreased by omeprazole 20 mg and lansoprazole 30 mg but not by rabeprazole 20 mg. Conversely, higher PPI dose (ie, omeprazole 80 mg) seemed to further decrease AUC(0-3h) of DOB in RMs but increased it in PMs. Omeprazole and lansoprazole at the standard doses inhibit CYP activity but rabeprazole does not, whereas high-dose omeprazole seems to induce CYPs.

13C-aminopyrine breath test accurately predicts long-term outcome of chronic hepatitis C.

BACKGROUND & AIMS: Although numerous non-invasive tests are currently available to explore liver function and disease activity in patients with HCV-related chronic diseases, none of these indicate the likelihood of disease progression in the individual patient. We aimed at assessing the prognostic ability of (13)C(2)-aminopyrine breath test ((13)C-ABT) in the prediction of liver fibrosis progression in patients with HCV chronic hepatitis who prospectively entered a long-term follow-up. METHODS: Fifty patients with HCV-related chronic disease who underwent paired liver biopsy (at baseline and after a mean period of 86 months) were included in the study. (13)C-ABT was carried out at baseline and every 3 years. Histological progression was defined as increase of at least 2 fibrosis units according to Ishak score. RESULTS: Fourteen patients progressed of at least 2 fibrosis units during the follow-up. These patients were more frequently infected with a HCV-1b genotype and had, at baseline, a significantly older age, higher BMI, AST levels, and AST to platelet ratio index (APRI). (13)C-ABT was altered in 57% of cases at baseline and in 100% of the cases at 3-year follow-up. In the univariate analysis, age (p=0.005), BMI (p=0.006), platelet count (p=0.03), AST (p=0.012) and ALT (p=0.04) levels, APRI (p=0.03), and baseline (13)C-ABT results (p<0.0001) were all independently associated with progression of liver fibrosis. By Cox's multiple regression analysis, the (13)C-ABT was the only covariate that significantly predicted liver fibrosis progression (HR 6.7; 95% CI 2.3-20.1; p<0.001). CONCLUSIONS: (13)C-ABT accurately predicts the risk of disease progression in patients with HCV-related chronic hepatitis.

Acid secretion-associated translocation of KCNJ15 in gastric parietal cells.

Potassium ions are required for gastric acid secretion. Several potassium channels have been implicated in providing K(+) at the apical membrane of parietal cells. In examining the mRNA expression levels between gastric mucosa and liver tissue, KCNJ15 stood out as the most highly specific K(+) channel in the gastric mucosa. Western blot analysis confirmed that KCNJ15 is abundant in the stomach. Immunofluorescence staining of isolated gastric glands indicated that KCNJ15 was expressed in parietal cells and chief cells, but not in mucous neck cells. In resting parietal cells, KCNJ15 was mainly found in puncta throughout the cytoplasm but was distinct from H(+)-K(+)-ATPase. Upon stimulation, KCNJ15 and H(+)-K(+)-ATPase become colocalized on the apical membranes, as suggested by immunofluorescence staining. Western blot analysis of the resting and the stimulated membrane fractions confirmed this observation. From nonsecreting preparations, KCNJ15-containing vesicles sedimented after a 4-h centrifugation at 100,000 g, but not after a 30-min spin, which did sediment most of the H(+)-K(+)-ATPase-containing tubulovesicles. Most of the KCNJ15 containing small vesicle population was depleted upon stimulation of parietal cells, as indicated by the fact that the KCNJ15 signal was shifted to a large membrane fraction that sedimented at 4,000 g. Our results demonstrate that, in nonsecreting parietal cells, KCNJ15 is stored in vesicles distinct from the H(+)-K(+)-ATPase-enriched tubulovesicles. Furthermore, upon stimulation, KCNJ15 and H(+)-K(+)-ATPase both translocate to the apical membrane for active acid secretion. Thus KCNJ15 can be added to the family of apical K(+) channels in gastric parietal cells.

Antisecretory actions of Baccharis trimera (Less.) DC aqueous extract and isolated compounds: analysis of underlying mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera (Less.) DC. (Asteraceae) is a species native to South America used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. Previous studies from this laboratory confirmed the antacid and antiulcer activities of the plant aqueous extract (AE) in rat and mouse models. AIM OF THE STUDY: To investigate the mechanisms involved in the antacid action of AE and isolated compounds from Baccharis trimera. MATERIALS AND METHODS: AE was assayed in vivo in cold-restraint stress gastric ulcers and in pylorus-ligated mice. Nine fractions (F2-F10) previously isolated from AE were assayed in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands, and on gastric microsomal H(+), K(+)-ATPase preparations. Chlorogenic acids (F2, F3, F6, F7), flavonoids (F9), an ent-clerodane diterpene (F8) and a dilactonic neo-clerodane diterpene (F10) have been identified in these fractions. RESULTS: Intraduodenal injection of AE (1.0 and 2.0 g/kg) in 4h pylorus-ligated mice decreased the volume (20 and 50%) and total acidity (34 and 50%) of acid secretion compared to control values. Administered orally at the same doses AE protected against gastric mucosal lesions induced in mice by restraint at 4°C. Exposure of isolated rabbit gastric glands to fractions F8 (10-100 µM) and F9 (10-300 µg/ml) decreased the basal [(14)C]-AP uptake by 50 and 60% of control (Ratio=6.2±1.1), whereas the remaining fractions were inactive. In the presence of the secretagogues F2 and F4 (30-300 µg/ml) decreased the [(14)C]-AP uptake induced by histamine (His) with a 100-fold lower potency than that of ranitidine. F5 and F6 reduced the [(14)C]-AP uptake stimulated by carbachol (CCh), but they were 10 to 20-fold less potent than atropine. F8 (diterpene 2) and F9 (flavonoids) decreased both the His- and CCh-induced [(14)C]-AP uptake, whereas F10 (diterpene 1) was inactive against the [(14)C]-AP uptake stimulated by secretagogues. Diterpene 2 was the most active of all tested compounds being 7-fold less potent than ranitidine and equipotent to atropine in reducing acid secretion in vitro. This compound also reduced the gastric H(+), K(+)-ATPase activity by 20% of control, while the remaining fractions were inactive on the proton pump in vitro. CONCLUSIONS: The results indicate that Baccharis trimera presents constituents that inhibit gastric acid secretion by acting mainly on the cholinergic regulatory pathway. The plant extract also contains compounds that exert moderate inhibition of the histaminergic regulatory pathway of acid secretion and the gastric proton pump. Altogether these active constituents appear to provide effective inhibition of acid secretion in vivo, which may explain the reputed antiulcer activity of the plant extract.

NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.

To understand the molecular basis of sequential N-dealkylation by cytochrome P450 2B enzymes, we studied the binding of amidopyrine (AP) as well as the metabolites of this reaction, desmethylamidopyrine (DMAP) and aminoantipyrine (AAP), using the X-ray crystal structure of rabbit P450 2B4 and two nuclear magnetic resonance (NMR) techniques: saturation transfer difference (STD) spectroscopy and longitudinal (T(1)) relaxation NMR. Results of STD NMR of AP and its metabolites bound to P450 2B4 were similar, suggesting that they occupy similar niches within the enzyme's active site. The model-dependent relaxation rates (R(M)) determined from T(1) relaxation NMR of AP and DMAP suggest that the N-linked methyl is closest to the heme. To determine the orientation(s) of AP and its metabolites within the P450 2B4 active site, we used distances calculated from the relaxation rates to constrain the metabolites to the X-ray crystal structure of P450 2B4. Simulated annealing of the complex revealed that the metabolites do indeed occupy similar hydrophobic pockets within the active site, while the N-linked methyls are free to rotate between two binding modes. From these bound structures, a model of N-demethylation in which the N-linked methyl functional groups rotate between catalytic and noncatalytic positions was developed. This study is the first to provide a structural model of a drug and its metabolites complexed to a cytochrome P450 based on NMR and to provide a structural mechanism for how a drug can undergo sequential oxidations without unbinding. The rotation of the amide functional group might represent a common structural mechanism for N-dealkylation reactions for other drugs such as the local anesthetic lidocaine.

Could metabolic liver function tests predict mortality on waiting list for liver transplantation? A study on 560 patients.

BACKGROUND: Allocation of graft in liver transplantation (LT) depends mainly on Model for End Stage Liver Disease (MELD) score. We studied the prognostic ability of three metabolic liver function tests in 560 cirrhotic patients listed for transplantation, in comparison with MELD and Child-Turcotte-Pugh (CTP) scores. METHODS: Indocyanine green retention rate (ICG), aminopyrine breath test (ABT), and galactose elimination capacity were performed at the time of listing in addition to standard biological parameters. Seventy-three patients died on waiting list, 438 were transplanted, and 73 died after LT. Cox regression analysis and receiver operating characteristic curves with c-statistics were calculated after stratification according to CTP and MELD score. RESULTS: For the mortality before transplantation, c-statistics showed that ICG and ABT had a slightly better prognostic ability (0.73 and 0.68, respectively) than MELD score (0.66), and similar to CTP score (0.70). ABT's prognostic ability remained significant once the MELD score (below and above 20) had already been taken into account. Only ICG had a prognostic ability to predict the survival after LT, even after stratification according to MELD and CTP score. CONCLUSIONS: Our results strongly support that ABT and ICG may be useful in the ranking of the patients in LT list, adding prognosis information in association with MELD score.

Rab27b localizes to the tubulovesicle membranes of gastric parietal cells and regulates acid secretion.

BACKGROUND & AIMS: Rabs are monomeric guanosine triphosphatases that regulate membrane trafficking and acid secretion in gastric parietal cells. Using a proteomics approach, we identified a new Rab, Rab27b, in tubulovesicle membranes and determined its role in parietal cell activation. METHODS: We used mass spectrometry (MS) to identify Rab27b in purified tubulovesicular membrane fractions and used immunoblot and immunofluorescence analyses to study its expression. Wild-type, constitutively active (Rab27bQ78L), and dominant negative (Rab27bN133I) forms of Rab27b were tagged with yellow fluorescent protein (YFP) and expressed in parietal cells using adenoviral constructs to study localization and function. Localization was visualized by fluorescence microscopy in resting and stimulated cells. Acid secretion in primary cell cultures was measured by aminopyrine accumulation. RESULTS: A tandem MS peptide mass fingerprint was matched to 7 peptides of Rab27b. Rab27b localized to tubulovesicle membranes, based on immunoblot and immunocytochemical analyses. Endogenous Rab27b, YFP/wild-type Rab27b, Rab27bQ78L, and Rab27bN133I all distributed throughout the cytoplasm of resting parietal cells. After stimulation, wild-type Rab27b and YFP-Rab27bQ78L translocated to the apical membrane, but YFPR-ab27bN133I did not. Expression of wild-type YFP-Rab27b or YFP-Rab27bQ78L did not affect acid secretion, whereas expression of Rab27bN133I almost completely inhibited acid secretion. CONCLUSIONS: Rab27b is associated with tubulovesicle membranes in the parietal cell and Rab27b may play a role in stimulation-associated membrane recruitment and gastric acid secretion.

Influence of chronic renal failure on acid secretion in isolated gastric mucosal cells from human biopsies.

It has been shown previously that the antisecretory response of famotidine (histamine H2-receptor antagonist) is altered in patients with renal failure. To evaluate the underlying mechanism(s) of this clinical observation we obtained biopsy specimens of fundic mucosa from two groups of patients with variable renal function (group 1 normal renal function (n = 8); group 2 renal insufficiency (n = 8), CL(CR) < 20 mL/min) [matched for age and sex]. Furthermore, we investigated the effect of intact parathyroid hormone (PTH (1-84)), urea and calcium on 14C-aminopyrine uptake as an indicator of acid secretion. Gastric mucosal cells from human biopsies were isolated by pronase and collagenase digestion. Cyclic AMP content of parietal cells was determined by radioimmunoassay. Histamine and calcium stimulated 14C-aminopyrine uptake. PTH (1-84) suppressed basal 14C-aminopyrine accumulation, whereas addition of urea had no influence either in presence or in absence of histamine. In contrast to histamine, PTH (1-84) did not induce a significant increase in cellular cyclic AMP. In conclusion, there is no difference in the activation of 14C-aminopyrine uptake between patients with normal renal function and renal insufficiency except lower basal values in patients with renal failure. This could be caused by PTH (1-84) and urea which inhibit gastric acid secretion. Only calcium is the important agent causing an increase in the sensitivity of parietal cells in hyperparathyroidism.

Noninvasive diagnosis and prognosis of liver cirrhosis: a comparison of biological scores, elastometry, and metabolic liver function tests.

BACKGROUND: Recently, noninvasive methods for the diagnosis of liver cirrhosis have been extensively developed. We assessed the accuracy of liver stiffness measurement, aspartate aminotransferase-to-platelet ratio index (APRI) score, 13C-aminopyrine breath test, and indocyanine green plasma clearance for the diagnosis of cirrhosis in patients with chronic liver disease and for the prediction of severe complications in cirrhotic patients. METHODS: A total of 296 consecutive patients with chronic liver diseases of various causes were studied. Diagnostic accuracy was assessed by receiver operating characteristic curve analysis. RESULTS: Areas under the receiver operating characteristic curve for the diagnosis of cirrhosis were (95% confidence interval) 0.93 (0.90-0.96) for liver stiffness measurement, 0.82 (0.77-0.87) for 13C-aminopyrine breath test, and 0.81 (0.76-0.86) for APRI score. Using cutoff values of 14.1 kPa for liver stiffness, 4.15% dose/h for 13C-aminopyrine breath test, and 1 for APRI score, the positive predictive value was approximately 90% for the diagnosis of cirrhosis. Using cutoff values of 65.2 kPa for liver stiffness, 1.17% dose/h for 13C-aminopyrine breath test, 2.82 for APRI score, and 51.1% for indocyanine green plasma clearance, the positive predictive value was approximately 80% for the occurrence of severe complications among cirrhotic patients. CONCLUSION: Liver stiffness measurement, 13C-aminopyrine breath test, indocyanine green plasma clearance, and APRI score are reliable noninvasive methods for the diagnosis of cirrhosis in patients with chronic liver diseases of various causes, and are also prognostic indicators for the occurrence of severe complications in cirrhotic patients.