Trypsinogen activation peptides assay in the early prediction of severity of acute pancreatitis

doi:10.1016/0140-6736(90)90135-R

The Lancet

Volume 335, Issue 8680, 6 January 1990, Pages 4-8

https://doi.org/10.1016/0140-6736(90)90135-R Get rights and content

Abstract

Trypsinogen activation can be quantified by measurement of released activation peptides (TAP assay). TAP assay in urine was performed on admission for 55 patients with acute pancreatitis. TAP concentration correlated with subsequent disease severity in 87%, whereas C-reactive protein concentration, and multifactorial scoring at 48 h, were correct in 55% and 84%. Sensitivity and specificity for TAP assay were 80% and 90%, for C-reactive protein 53% and 55%, and for multifactorial scoring at 48 h, 60% and 93%. Urine TAP assay distinguishes acute pancreatitis without trypsinogen activation from acute pancreatitis with trypsinogen activation, and helps to identify patients who will progress to the severe acute disease. Use of the assay should allow early intensive treatment of those who need it.

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Pancreatitis is characterized by acinar cell death and persistent inflammation. Ferroptosis is a type of lipid peroxidation-dependent necrosis, which is negatively regulated by glutathione peroxidase 4. We studied how trypsin, a serine protease secreted by pancreatic acinar cells, affects the contribution of ferroptosis to triggering pancreatitis.
In vitro, the mouse pancreatic acinar cell line 266-6 and mouse primary pancreatic acinar cells were used to investigate the effect of exogenous trypsin on ferroptosis sensitivity. Short hairpin RNAs were designed to silence gene expression, whereas a library of 1080 approved drugs was used to identify new ferroptosis inhibitors in 266-6 cells. In vivo, a Cre/LoxP system was used to generate mice with a pancreas-specific knockout of Gpx4 (Pdx1-Cre;Gpx4^flox/flox mice). Acute or chronic pancreatitis was induced in these mice (Gpx4^flox/flox mice served as controls) by cerulein injections or a Lieber–DeCarli alcoholic liquid diet. Pancreatic tissues, acinar cells, and serum were collected and analyzed by histology, immunoblot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, or immunohistochemical analyses.
Supraphysiological doses of trypsin (500 or 1000 ng/mL) alone did not trigger significant cell death in 266-6 cells and mouse primary pancreatic acinar cells, but did increase the sensitivity of these cells to ferroptosis upon treatment with cerulein, L-arginine, alcohol, erastin, or RSL3. Proteasome 26S subunit, non–adenosine triphosphatase 4–dependent lipid peroxidation caused ferroptosis in pancreatic acinar cells by promoting the proteasomal degradation of glutathione peroxidase 4. The drug screening campaign identified the antipsychotic drug olanzapine as an antioxidant inhibiting ferroptosis in pancreatic acinar cells. Mice lacking pancreatic Gpx4 developed more severe pancreatitis after cerulein infection or ethanol feeding than control mice. Conversely, olanzapine administration protected against pancreatic ferroptotic damage and experimental pancreatitis in Gpx4-deficient mice.
Trypsin-mediated sensitization to ferroptotic damage increases the severity of pancreatitis in mice, and this process can be reversed by olanzapine.
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Advanced stages of chronic pancreatitis and pancreatic cancers (PCs) are very serious diseases with very poor prognosis. Therefore, identification of reliable and specific biomarker(s) at early stages of the diseases could be key to their early prevention and therapy. In this chapter, currently used and putative biomarkers of acute and chronic pancreatitis and PC are summarized. Total serum lipase and/or amylase are most widely used biomarkers of acute pancreatitis; lipase assay being more sensitive and specific than that of amylase. Imaging technologies provide key support for the diagnosis of both acute and chronic pancreatitis. Biomarkers of chronic pancreatitis are poorly developed and remain challenging because of impaired secretory components of exocrine pancreas. The focus of future clinical diagnosis of chronic pancreatitis and PC lies in identification of biomarkers using omics and microRNA arrays along with imaging technologies in well-defined experimental models and their validation in patients diagnosed with various stages of chronic pancreatitis and PC.
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Prediction of the severity of acute pancreatitis on admission by carboxypeptidase-B activation peptide: A systematic review and meta-analysis
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The assessment of acute pancreatitis severity on admission currently remains a challenge to clinicians. A single, rapid biochemical marker would be preferable to clinical and radiological scoring systems. The aim of this study was to undertake a meta-analysis on the value of carboxypeptidase-B activation peptide (CAPAP) in predicting severity of acute pancreatitis on admission.
Major databases and trial registries were searched to identify all relevant studies from January 1998 to March 2015. Pooled sensitivity, specificity and the diagnostic odds ratios (DOR) with 95% confidence interval (CI) were calculated for each study and were compared to other biomarkers, if included, within the same study. Summary receiver-operating curves (ROC) were conducted and the area under the curve (AUC) was evaluated.
In total, six studies were included. At the time of admission, the AUC of serum CAPAP for predicting severity of acute pancreatitis was 0.86 with pooled sensitivity, specificity and DOR of 0.90, 0.70 and 19.08, respectively. When serum CAPAP was compared with urinary CAPAP, the AUC, pooled sensitivity, specificity and DOR were 0.69 vs 0.88, 0.90 vs 0.81, 0.68 vs. 0.77 and 17.96 vs. 18.58, respectively. Similarly, the AUC, pooled sensitivity, specificity and DOR of serum CAPAP vs maximal serum C-reactive protein within the first 3 days of admission were found to be 0.97 vs. 0.82, 0.92 vs. 0.88, 0.81 vs 0.68 and 37.90 vs. 18.80, respectively.
Both serum and urinary CAPAP have the potential to act as a stratification marker on admission in predicting severity of acute pancreatitis.

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MEDICAL SCIENCETrypsinogen activation peptides assay in the early prediction of severity of acute pancreatitis

Abstract

J Immunol Methods

Clin Chim Acta

Gastroenterology

Activation of pancreatic zymogens

Dig Dis Sci

A rational approach to the specific chemotherapy of pancreatitis

Scand J Gastroenterol

Pathogenesis of acute pancreatitis

Annu Rev Med

Two human trypsinogens: purification, molecular properties and the N-terminal sequences

Biochemistry

MEDICAL SCIENCE
Trypsinogen activation peptides assay in the early prediction of severity of acute pancreatitis