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1.
Blunted Evoked Prouroguanylin Endocrine Secretion in Chronic Constipation.
Waldman, SA, Tenenbaum, R, Foehl, HC, Winkle, P, Griffin, P
Clinical and translational gastroenterology. 2019;(7):e00016
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Abstract
OBJECTIVES Prouroguanylin (ProUGN) in the intestine is cleaved to form uroguanylin (UGN), which stimulates guanylate cyclase C (GUCY2C), inducing cyclic guanosine monophosphate signaling. Paracrine release regulates fluid secretion, contributing to bowel function, whereas endocrine secretion evoked by eating forms a gut-brain axis, controlling appetite. Whereas hormone insufficiency contributes to hyperphagia in obesity, its contribution to the pathophysiology of constipation syndromes remains unexplored. Here, we compared circulating ProUGN and UGN in healthy subjects and in patients with chronic idiopathic constipation (CIC) and patients with irritable bowel syndrome with constipation (IBS-C). METHODS Circulating ProUGN and UGN levels were measured in 60 healthy subjects, 53 patients with CIC, and 54 patients with IBS-C. After an overnight fast, the participants ingested a standardized meal; blood samples were drawn at fasting and at 30, 60, and 90 minutes thereafter, and hormone levels were quantified by enzyme-linked immunosorbent assay. RESULTS Fasting ProUGN levels were >30% lower in patients with CIC and those with IBS-C compared with healthy subjects regardless of age, sex, or disease state. After eating, ProUGN levels increased compared with fasting levels, although the rate of change was slower and maximum levels were lower in patients with CIC and those with IBS-C. Similarly, fasting UGN levels were lower in patients with CIC and those with IBS-C compared with healthy subjects. However, unlike ProUGN levels, UGN levels did not increase after eating. DISCUSSION These observations support a novel pathophysiologic model in which CIC and IBS-C reflect a contribution of ProUGN insufficiency dysregulating intestinal fluid and electrolyte secretion. TRANSLATIONAL IMPACT This study suggests that CIC and IBS-C can be treated by oral GUCY2C hormone replacement. Indeed, these observations provide a mechanistic framework for the clinical utility of oral GUCY2C ligands like plecanatide (Trulance) and linaclotide (Linzess) to treat CIC and IBS-C.
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Association of intestinal permeability with a NUTRIC score in critically ill patients.
Eslamian, G, Ardehali, SH, Vahdat Shariatpanahi, Z
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:1-8
Abstract
OBJECTIVES The aim of this study was to investigate the association of intestinal permeability with the Nutrition Risk in Critically Ill (NUTRIC) score and the modified NUTRIC score (mNUTRIC) in intensive care unit (ICU) hospitalized patients. METHODS One hundred and fifty ICU hospitalized adult patients admitted between October 2017 and April 2018 who stayed for >24 h in the general ICU were enrolled in the study. Nutrition status was estimated using the NUTRIC score, an ICU-specific nutrition risk assessment tool. The NUTRIC score was calculated using the exact same thresholds and point system as developed previously. Admission plasma endotoxin and zonulin concentrations were measured to assess intestinal permeability. RESULTS Median plasma endotoxin and zonulin increased with increasing mNUTRIC and NUTRIC categories in the overall study population and in the glutamine-deficient subgroup. Multivariate binary logistic regression analyses showed a significant association between the plasma endotoxin (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.8-3.52) and zonulin (OR, 1.11; 95% CI, 1.03-1.20) levels with NUTRIC category in the overall population and the glutamine-deficient subgroup. Similar results were obtained when using mNUTRIC. CONCLUSIONS Results from the present study provided evidence that higher plasma endotoxin and zonulin levels are associated with a progressively higher NUTRIC score in critically ill patients.
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Protein Induced by Vitamin K Absence II (PIVKA-II) as a potential serological biomarker in pancreatic cancer: a pilot study.
Tartaglione, S, Pecorella, I, Zarrillo, SR, Granato, T, Viggiani, V, Manganaro, L, Marchese, C, Angeloni, A, Anastasi, E
Biochemia medica. 2019;(2):020707
Abstract
INTRODUCTION Protein induced by vitamin K absence II (PIVKA-II) is an abnormal prothrombin increased in gastrointestinal malignancy. We aimed to evaluate PIVKA-II in comparison to established pancreatic cancer (PC) biomarkers (CA 19-9, carcinoembryonic antigen (CEA) and CA 242) measured in PC patients and in patients with benign pancreatic diseases. MATERIALS AND METHODS We studied 26 PC patients (Group 1) and 20 patients with benign pancreatic diseases (Group 2). PIVKA-II and CEA were measured by chemiluminescent enzyme immunoassay method (CLEIA) on LUMIPULSE G1200 (Fujirebio-Europe, Gent, Belgium), CA 19-9 and CA 242 were measured by ELSA (CisBio Bioassays, Codolet, France) and EIA (Fujirebio Diagnostics AB, Göteborg, Sweden), respectively. Receiver operating characteristic (ROC) analysis was performed to assess biomarkers' diagnostic characteristics in both groups. RESULTS Median and interquartile range (IQR) in Group 1 and Group 2 were: 1749.0 (320.2 - 3921.0) vs. 31.0 (23.0 - 43.0) mAU/mL (P < 0.001) for PIVKA-II, 260.0 (158.7 - 272.0) vs. 45.2 (9.0 - 58.0) U/mL (P = 0.034) for CA 19-9, 104.0 (30.2 - 150.0) vs. 7.2 (4.8 - 26.0) U/mL (P < 0.050) for CA 242, 9.4 (5.3 - 37.5) vs. 4.5 (1.8 - 7.0) ng/mL (P = 0.021) for CEA. Areas under the ROC curve of PIVKA-II, CA 19-9, CA 242, CEA were 0.86 (95% CI: 0.71 - 1.00), 0.58 (95% CI: 0.38 - 0.78), 0.73 (95% CI: 0.54 - 0.92), 0.64 (95% CI: 0.44 - 0.85), respectively. CONCLUSIONS PIVKA-II is significantly higher in PC than in benign pancreatic diseases. PIVKA-II shows a rather good diagnostic performance compared to CA 19-9, CEA and CA242, thus its determination could help PC management.
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Update on hypoparathyroidism.
Cusano, NE, Bilezikian, JP
Current opinion in rheumatology. 2019;(4):381-387
Abstract
PURPOSE OF REVIEW Hypoparathyroidism is a rare endocrine disorder characterized by low or insufficient parathyroid hormone (PTH) concentrations leading to hypocalcemia, hyperphosphatemia, and markedly reduced bone turnover. Despite being a rare disease, hypoparathyroidism has a profound impact on affected patients. RECENT FINDINGS Recent epidemiologic surveys demonstrate a prevalence of between 5.3 and 40/100 000, confirming the orphan status of this disease. There is a female predominance, and anterior neck surgery is the most common etiology. Recent studies have better elucidated the chronic manifestations of the disease, impacting quality of life and multiple organ systems including the renal, cardiovascular, and skeletal systems. There are now data on longer term use of parathyroid hormone (PTH) and PTH analogs. SUMMARY This review focuses on recent contributions to the literature on the prevalence and epidemiology of the disease, risk of chronic manifestations, and treatment with PTH(1-34) and rhPTH(1-84). Further research is needed to determine the pathophysiology of complications in hypoparathyroidism and whether interventions can decrease future risk of these complications. In addition, further data are needed with regards to more physiologic dosing regimens and long-term treatment with PTH and PTH analogs.
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Vitamin K deficiency in critical ill patients; a prospective observational study.
Dahlberg, S, Schurgers, L, Schött, U, Kander, T
Journal of critical care. 2019;:105-109
Abstract
BACKGROUND Vitamin K is a cofactor for proteins involved in cardiovascular health, bone metabolism and cancer. Measuring uncarboxylated prothrombin, also termed as "protein induced by vitamin K absence or antagonism for factor II (PIVKA-II)", has been used to assess vitamin K status. High levels may indicate vitamin K deficiency. The aim of this study was to measure PIVKA-II and prothrombin time (PT-INR) in intensive care (ICU) patients and correlate vitamin K status with mortality. METHODS Ninety-five patients admitted to the ICU had blood samples taken near admission and every third day. In addition to PIVKA-II and PT-INR, critical-care severity scores were computed. RESULTS The median baseline PIVKA-II was 4.97 μg/L compared to the upper reference of 2.0 μg/L. PIVKA-II further increased at days 3 and 6, (median 7.88 μg/L, p = .047 and median 8.14 μg/L, p = .011) predominantly in cardiac arrest patients (median 21.4 μg/L, day 3). CONCLUSION Intensive care patients have increased PIVKA-II levels at admission, which increases during the ICU stay, especially in cardiac arrest patients. There were no correlations between PIVKA-II and PT-INR, SOFA score or mortality. Further studies are needed to determine why PIVKA-II increases and whether high PIVKA-II levels in ICU patients affect long-term mortality or morbidity.
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Prognostic value of PIVKA-II in hepatocellular carcinoma patients receiving curative ablation: A systematic review and meta-analysis.
Zhang, D, Liu, Z, Yin, X, Qi, X, Lu, B, Liu, Y, Hou, J
The International journal of biological markers. 2018;(3):266-274
Abstract
BACKGROUND Several studies have been conducted to evaluate the prognostic value of prothrombin induced by vitamin K absence-II (PIVKA-II) overexpression in hepatocellular carcinoma patients treated with curative ablation. However, the results remain controversial. The purpose of this meta-analysis was to explore the correlation between PIVKA-II expression and survival outcomes in these patients. METHODS We performed a systematic literature search in PubMed, EMBASE, Medline, Cochrane Library, and Web of Science to identify the relevant articles investigating the prognostic value of PIVKA-II in patients with hepatocellular carcinoma. Combined hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival and recurrence-free survival were calculated as the analysis endpoints. RESULTS A total of 15 cohorts encompassing 5647 patients were included. The results indicated that elevated PIVKA-II was significantly associated with poorer overall survival (HR 1.59; 95% CI 1.40, 1.82; P < 0.001) and recurrence-free survival (HR 1.76; 95% CI 1.42, 2.17; P < 0.001). Similar results were observed in the subgroup analysis based on sample size, analytical method, treatment modality, and cut-off value. CONCLUSIONS This meta-analysis suggests that elevated PIVKA-II is a predictor of unfavorable overall survival and recurrence-free survival in hepatocellular carcinoma patients receiving curative ablation. More rigorous studies are warranted to confirm the clinical utility of PIVKA-II in determining hepatocellular carcinoma prognosis.
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Proenkephalin for the early detection of acute kidney injury in hospitalized patients with chronic kidney disease.
Breidthardt, T, Jaeger, C, Christ, A, Klima, T, Mosimann, T, Twerenbold, R, Boeddinghaus, J, Nestelberger, T, Badertscher, P, Struck, J, et al
European journal of clinical investigation. 2018;(10):e12999
Abstract
BACKGROUND The early detection of acute kidney injury (AKI) in patients with chronic kidney disease (CKD) is an unmet clinical need. Proenkephalin (PENK) might improve the early detection of AKI. METHODS One hundred and eleven hospitalized CKD patients undergoing radiographic contrast procedures were enrolled. PENK was measured in a blinded fashion at baseline (before contrast media administration) and on day 1 (after contrast media administration). The potential of PENK levels to predict contrast-induced AKI was the primary endpoint. RESULTS Baseline creatinine and baseline PENK were similar in AKI and no-AKI patients. In AKI patients, day 1 PENK (198 pmol/L vs 121 pmol/L, P < 0.01) was significantly higher compared to no-AKI patients. The area under the curve (AUC) for the prediction of AKI by day 1 PENK was 0.79, 95% CI: 0.70-0.87, similar to serum creatinine: 0.78, 95% CI: 0.61-0.95. Delta PENK was significantly higher in AKI compared to no-AKI patients (53 pmol/L vs 1 pmol/L, P < 0.01). The AUC for the prediction of AKI by delta PENK was high (0.92, 95%CI 0.82-1.00) and remained high for creatinine-blind AKI (0.94, 95% CI: 0.87-0.97). CONCLUSION Delta PENK levels improve the early detection of contrast-induced AKI in CKD patients over serial creatinine sampling. Delta PENK accelerates the detection of creatinine-blind AKI by 24 hours.
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Glycated hemoglobin A1c level on the day of emergency surgery is a marker of premorbid glycemic control: a retrospective observational study.
Hokka, M, Egi, M, Mizobuchi, S
BMC anesthesiology. 2018;(1):180
Abstract
BACKGROUND Current international guideline recommends to maintain blood glucose level ≤ 180 mg/dL in acute ill patients, irrespective of presence of premorbid diabetes. However, there are studies suggested that optimal acute glycemic control should be adjusted according to premorbid glycemic control in patients with chronic hyperglycemia. Accordingly, to obtain the information of premorbid glycemic control would be relevant. However, the HbA1c level on the day of the emergency operation (HbA1c-ope) might not be useful as a surrogate of premorbid chronic glycemic control, since glucose metabolism can be affected by inflammation, severity of illness and surgical invasion. METHODS We hypothesized that HbA1c-ope reflects pre-morbid glycemic control. To assess this hypothesis, we conducted a single-center retrospective observational study to assess the association between HbA1c-ope and HbA1c level measured within 30 days before the operation (HbA1c-pre). We screened patients who had been admitted to the ICU of our hospital after emergency surgery during the period from January 2008 to December 2016. Patients in whom both of HbA1c-ope and HbA1c-pre were measured were included in this study. We compared HbA1c-ope and HbA1c-pre using the paired t-test. The correlation between the two HbA1c measurements was assessed using Pearson's correlation coefficient. Its agreement was assessed using the Bland-Altman approach with 95% confidence intervals. RESULTS We included 48 patients in this study. The mean value of HbA1c-pre was 6.3%, which was not significantly different from the mean value of 6.2% for HbA1c-ope (p = 0.12). There was a significant correlation between HbA1c-pre and HbA1c-ope (r2 = 0.70, p < 0.001). The mean difference between two HbA1c measurements was 0.12% (95% CI: -0.03% to 0.27%). The limit of agreement ranged from - 0.9% to +1.1%. CONCLUSIONS We found that there was a significant correlation between HbA1c-ope and HbA1c-pre. Our findings suggest that HbA1c-ope can be used to estimate previous glycemic control with an acceptable degree of accuracy, enabling personalized glycemic control in the perioperative period.
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Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for hepatocellular carcinoma detection: a meta-analysis.
Caviglia, GP, Ribaldone, DG, Abate, ML, Ciancio, A, Pellicano, R, Smedile, A, Saracco, GM
Scandinavian journal of gastroenterology. 2018;(6):734-740
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Abstract
OBJECTIVES In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development. MATERIALS AND METHODS We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA). RESULTS A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746-0.837) and 0.767 (0.732-0.803), respectively. The combination of PIVKA-II + AFP results in a sAUC of 0.859 (0.837-0.882). The performance for HCC detection of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.068, p = .032 and ΔsAUC = 0.092, p < .001, respectively). CONCLUSION In clinical practice, the use of PIVKA-II + AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.
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Review on Vitamin K Deficiency and its Biomarkers: Focus on the Novel Application of PIVKA-II in Clinical Practice.
Dong, R, Wang, N, Yang, Y, Ma, L, Du, Q, Zhang, W, Tran, AH, Jung, H, Soh, A, Zheng, Y, et al
Clinical laboratory. 2018;(4):413-424
Abstract
BACKGROUND Vitamin K (VK) is a co-factor of the γ-glutamyl carboxylase that catalyzes the conversion of glutamate residues to γ-carboxyglutamate in VK-dependent proteins. The carboxylation reaction imparts the essential calcium-binding residues for the biological function of several proteins involved in the process of coagulation and bone metabolism. VK deficiency is frequently encountered in newborns and can lead to fatal hemorrhagic complications. This review describes and discusses the clinical application of VK deficiency testing. METHODS References and data were researched in PubMed and reviewed. RESULTS In adults, VK deficiency is associated with uncontrolled bleeding, liver dysfunction, osteoporosis, and coronary diseases. An improved understanding of the role of VK deficiency in health and illness can be achieved by setting a gold-standard in the inter-laboratory estimations of VK. However, conventional methods used to measure the VK deficiency based upon the coagulation time lack sensitivity and specificity. Recently, the alterations in proteins induced by VK absence or antagonism (PIVKA) have proven to be suitable biomarkers for detecting VK deficiency. The measurement of PIVKA-II exhibits an enhanced sensitivity and specificity in comparison to other methods conventionally used for the assessment of VK deficiency in newborns and adults. CONCLUSIONS PIVKA-II could potentially be employed as an effective biomarker in the diagnosis of VK deficiency.