W. Uhl

Serum levels of procarboxypeptidase B and its activation peptide in patients with acute pancreatitis and non-pancreatic diseases

Background: Carboxypeptidase B from the pancreatic gland may exist in three different molecular and immunoreactive forms: the proenzyme, the active enzyme, and the activation peptide. Aims: To investigate levels of procarboxypeptidase B (proCAPB) and its activation peptide in serum in acute pancreatitis to test the accuracy of these two variables as markers for the diagnosis of acute pancreatitis and for prediction of pancreatic necrosis. To elucidate whether leakage of proenzymes and activation of proenzymes reflect two different pathophysiological events in acute pancreatitis. Methods: Sera from patients with acute pancreatitis (n=85) and acute abdominal pain of non-pancreatic origin (n=53) were analysed for proCAPB and its activation peptide. Patients with pancreatitis were divided into necrotising (n=33) and oedematous attacks (n=52) using contrast enhanced computed tomography. Accuracy was determined using receiver operating characteristic curve analysis. Results: Immunoreactive carboxypeptidase B activation peptide (ir-CAPAP) concentration in serum on admission was 0.7 nmol/l (0–18.1) in patients with oedematous pancreatitis compared with 5.8 nmol/l (1.9–34) in patients with later development of pancreatic necrosis. Elevated levels of the activation peptide on admission correlated with an accuracy of 92% to later development of pancreatic necrosis. Ir-proCAPB concentration in serum on admission was 16.0 nmol/l (1.4–50.5) in all patients with acute pancreatitis versus 0.3 nmol/l (0–3.6) in patients with non-pancreatic acute abdominal disorders. Cases with oedematous pancreatitis had ir-proCAPB levels of 15.4 nmol/l (1.4–50.5) versus 19.1 nmol/l (2.7–36.1) in cases with later development of pancreatic necrosis. Measurement of the proenzyme can thus be useful for the diagnosis of acute pancreatitis (accuracy 99%) but levels did not correlate with later development of pancreatic necrosis (accuracy 56%). Conclusion: Leakage of proenzymes occurs in acute pancreatitis, irrespective of severity, while development of pancreatic necrosis occurs only when there is activation of the proenzymes.

Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans

Background and aim: The aim of this study was to systematically analyse the pattern of regeneration in human acute pancreatitis by testing whether pancreatic stellate cells, their myofibroblastic offspring, and pancreatic ductules are involved in the regenerative process. Patients and methods: Between January 1994 and November 2000, 24 necrosectomy specimens containing vital tissue were obtained for pathological examination. Formalin fixed tissue samples were routinely processed and immunostained for cytokeratins 7 and 19, smooth muscle actin, desmin, Ki-67, and CD68. Pancreatic tissue from organ donors served as normal controls. Results: Necrosectomy specimens were obtained between 11 and 41 days after the onset of symptoms. In vital areas of necrosectomy samples, spherical hypercellular spheres consisting of loose vascular connective tissue occurred, in part showing duct-like profiles which sprouted from remnant exocrine tissue almost perpendicular to the periphery of the spheres. In normal tissue, only a few stellate cells and myofibroblasts were present around ducts and ductules. In contrast, numerous stellate cells and myofibroblasts were detected in the hypercellular regenerative spheres after acute pancreatitis, both being situated within the loose tissue and forming compact periductular sheaths. Stellate cells/myofibroblasts and ductule cells exhibited increased proliferative activity. Conclusions: Pancreatic stellate cells and their activated myofibroblastic offspring may participate in regeneration after acute necrotising pancreatitis in humans. Time course studies are needed to further strengthen this regeneration concept.

Protease-Antiprotease Interactions and the Rationale for Therapeutic Protease Inhibitors

A number of pancreatic enzymes have been suggested as the initiating factor for acute pancreatitis. In particular, the relationship between proteases and antiproteases has been examined extensively, based on the suspicion that an imbalance between them is the central factor in the pathogenesis of acute pancreatitis. Animal studies with antiproteolytic agents in models of acute pancreatitis have shown an improvement in outcome. However, more recently, prospective, randomized, multicentre trials treating human acute pancreatitis with antiproteolytic drugs (aprotinin, gabexate mesilate, and even fresh frozen plasma) have failed to show any benefit in the clinical setting. Thus, clinically, it seems likely that antiproteolytic therapy has no effect on the course of severe acute pancreatitis. Today, the mortality in severe acute pancreatitis is determined by septic complications due to infected pancreatic necroses in the late phase 2-3 weeks after the onset of the disease. Death in the early phase of the disease has become increasingly rare where an imbalance between proteases and antiproteases may be involved.

Human pancreas-specific protein. A diagnostic and prognostic marker in acute pancreatitis and pancreas transplantation.

SummaryConclusionHuman pancreas-specific protein (hPASP) is a very sensitive reflector of the extent of pancreatic necrosis on the cellular level, and is of both diagnostic and prognostic value in acute pancreatitis. Furthermore, it allows the estimation of the severity of graft pancreatitis soon after simultaneous renal and pancreatic transplantation.BackgroundDiagnosis of acute pancreatitis (AP) has been improved in the past 15 yr as new methods for the determination of specific pancreatic enzymes have been developed. However, these enzymes have no prognostic implications. In this prospective study, we evaluated the role of human pancreas-specific protein (hPASP) in comparison with pancreatic amylase and C-reactive protein (CRP) in acute pancreatitis and pancreas transplantation.Patients and MethodsThe study included 40 patients (22 female, 18 male; mean age 51 yr, range 22–88 yr) with AP and 7 patients (2 female, 5 male; mean age 37 yr, range 25–49 yr) with type I diabetes and renal insufficiency who underwent simultaneous kidney and pancreas transplantation. By means of contrast-enhanced computed tomography (CT) and/or intraoperative findings, patients were judged to have edematous-interstitial (AIP,n=20, mean age 55.2 yr, range 24–88 yr) or necrotizing pancreatitis (NP,n=20, mean age 46.3 yr, range 22–81 yr). Serum hPASP concentration was measured daily by a commercial radioimmunoassay technique. In 25 healthy subjects and in several control groups (35 patients with chronic pancreatitis, 20 patients with pancreatic carcinoma and 80 patients with different gastrointestinal diseases) a single blood specimen was taken at hospital admission for the determination of the normal range of hPASP and for specificity analysis.ResultsThe upper normal value for hPASP in healthy subjects was found to be 52 ng/mL. Serum hPASP was elevated in all patients suffering from AP, with a median of 343 ng/mL (lower-upper quartile: 192–478 ng/mL) at hospital admission. In the daily serum monitoring with respect to the onset of symptoms, significantly higher hPASP levels were found in NP compared with AIP after day 2 (p<0.001). In patients with NP, peak values of hPASP correlated significantly with the extent of pancreatic necroses measured by contrast-enhanced CT-scanning, whereas CRP did not. Six patients of the transplantation group had the same serum hPASP course as AIP, with almost normal values on the third postoperative day. One patient had elevated levels throughout the observation period. This patient suffered from necrotizing graft pancreatitis, confirmed by relaparotomy, and died because of subsequent septic complications.

A Study on the Activation Peptide Released from Procarboxypeptidase B (CAPAP) and Anionic Trypsinogen in Patients with Acute Abdominal Disorders of Non-Pancreatic Origin

Background: The activation peptide released from procarboxypeptidase B, CAPAP, is a marker of the activation of pancreatic enzymes in acute pancreatitis while anionic trypsinogen (AT) levels in urine relate to leakage of unactivated proenzymes. Data on these markers in patients suffering from severe acute abdominal disorders of non-pancreatic origin are lacking. Purpose: To examine levels of CAPAP and AT in serum and urine from patients with severe acute abdominal disorders of non-pancreatic origin in order to better define the diagnostic specificity of these two markers in severe acute pancreatitis in relation to other acute intra-abdominal disorders. Subjects and Methods: The study included 54 patients with severe acute abdominal disorders of non-pancreatic origin with an APACHE II score >3. Immunoreactive CAPAP (irCAPAP) and immunoreactive AT (irAT) were measured in serum and urine using specific immunoassays. Results: In urine, irCAPAP levels were mildly increased (>2 nmol/l) in 13% of the patients with severe acute abdominal diseases of non-pancreatic origin, but on no occasion did the increase approach the cutoff levels described for severe acute pancreatitis (>100 nmol/l). However, irAT levels in serum and urine were increased (>50 µg/l) in 54% of the cases. Conclusion: Contrary to what is found for irAT, patients with acute abdominal pain of non-pancreatic origin rarely have markedly increased levels of irCAPAP in serum and urine.

A Decade of Octreotide

complications following pancreatic surgery). Somatostatin analogues including octreotide have been shown to reduce pressure in the splanchnic circulation, an effect that was exploited in the management of variceal and nonvariceal hemorrhages. Despite a widespread therapeutic application, octreotide seems to be a safe drug free of major side effects. Somatostatin, a peptide hormone initially isolated from ovine hypothalami, has been documented to inhibit the release of growth hormone. It soon became evident that this peptide was not only present in the brain but was widely distributed in the stomach, the gastrointestinal tract and the pancreas. By 1980, the gene encoding for prosomatostatin had been identified and it became eviMost of the reported side effects are gastrointestinal in dent that different molecular forms are present in the nature and include steatorrhea, bloating, minor nausea, body. Later on, different receptors for somatostatin were gallstones and mild forms of glucose intolerance. Recently identified and it became clear that the different molecular a new formulation of octreotide, octreotide LAR (longforms and the different receptors are part of a complicated acting repeatable), was developed which enables once-acontrol system which regulate a variety of body functions. month administration. Octreotide LAR combines over a Somatostatin molecules exert profound inhibitory funcdecade of proven benefits of the subcutaneous octreotide tions, not only on growth hormone secretion but also on administration with a more convenient formulation for many gastrointestinal functions. These different effects long-term treatment of a variety of diseases. Onceform the basis for an enormous therapeutic potential of monthly administration should improve patient acceptasomatostatin in different diseases. The short half-life of bility and compliance; it represents a significant advance natural somatostatin which necessitates a continuous inin the management of a number of conditions associated travenous infusion has made it difficult to transform the with excessive peptide secretion (acromegaly, neuroendonatural peptide into a successful drug. It was therefore a crine tumors). There is no doubt that additional indicamajor step forward when a synthetic analogue of somatotions will emerge as investigations continue. Treatment of statin, octreotide, was synthesized and became available certain gastrointestinal cancers and prevention of variceal for clinical use in the mid-eighties. For over a decade, bleeding are two clinical areas which are currently under subcutaneous octreotide has proven effective in the treatinvestigation. A decade of octreotide has been beneficial ment of acromegaly and in several clinical areas relating for many patients; hopefully many more will be able to to gastroenterology and digestive surgery. The ability of take advantage of this fascinating peptide. octreotide to control symptoms such as diarrhea or flush caused by gut-neuroendocrine tumors soon became evident. Subsequently, octreotide was used in other forms of secretory diarrhea (AIDS-related diarrhea, idiopathic Bern and Basel Markus W. Buchler diarrhea, diabetic diarrhea) but also in the management January 1999 Christoph Beglinger of pancreatic disorders (pancreatic fistulae, prevention of