Role of Pancreatic Enzymes in Acute Pancreatitis

Role of Pancreatic Enzymes in Acute Pancreatitis M. V. SINGER, P. LAYER, and H. GOEBELL 1 Despite extensive clinical and experimental studies, the pathophysiology of acute pancreatitis is still poorly understood. Although in 80% of patients pancreatitis is associated with biliary tract disease and alcohol abuse, the precise mechanisms of induction and progression of pancreatic injury remain uncertain. There is clini cal and experimental evidence that intrapancreatic activation of digestive en zymes, and the subsequent "autodigestion", is the common underlying patholog ical process for damage to the pancreas in acute pancreatitis [4]. However, one of the major mysteries of this disease remains unanswered, that is, how and where, within the pancreas, do digestive enzymes become activated during pancreatitis? We are still looking for the trigger mechanism of pancreatitis. In addition, we do not know whether the cardiac, pulmonary, and renal complications during acute pancreatitis are caused by the circulating pancreatic enzymes. Alternatively, these complications might be caused by toxic substances released from the inflamed pancreas or merely be a nonspecific response of different organs to severe intraab dominal inflammation. In the present paper we shall give a short review of the pathogenetic role of pancreatic enzymes in acute pancreatitis. Three main areas will be discussed: 1. Why is it that intrapancreatic activation of pancreatic enzymes does not occur under normal conditions? What are the protective mechanisms? 2. What are the trigger mechanisms of intrapancreatic activation of digestive en zymes? 3. What happens when digestive enzymes are activated? What are the damaging actions of the individual enzymes? Protective Mechanisms The pancreas protects itself against the potentially harmful effects of its own di gestive enzymes in several ways. 1. All enzymes which can digest membranes (e.g., trypsin, chymotrypsin, car boxypeptidase, elastase, and phospholipase A) are synthesized and secreted as inactive precursors or zymogens and the activation of these zymogens nor mally occurs only after they have been secreted into the duodenum. Enzymes which do not attack membranes (e.g., amylase, lipase) are secreted in active forms. 1 Div. of Gastroenteroiogy, Dept. of Medicine, University of Essen, D-4300 Essen/FRG. Diagnostic Procedures in Pancreatic Disease Ed. by P. Malfertheiner and H. Ditschuneit © Springer-Verlag Berlin Heidelberg 1986 68 M. V. Singer et al. 2. The enzymes are stored in zymogen granules which are isolated from sur rounding compartments of the acinar cell by phospholipid membranes. Should zymogens become inadvertently activated, their containment within membrane-enclosed intracellular spaces would, presumably, prevent cell in JUry. 3. The acinar cell also synthesizes a trypsin inhibitor which blocks any trypsin which is inadvertently present in the acinar cell. Not only pancreatic tissue, but also pancreatic juice and serum contain proteolytic enzyme inhibitors (e.g., pancreatic trypsin inhibitor, alpha-I-antitrypsin, alpha-2-macroglobin [20]). Should trypsinogen become prematurely activated within the acinar cell, these trypsin inhibitors would be expected to bind and inactivate trypsin and, thus, prevent further zymogen activation within the cell. 4. The activating enzyme (enterokinase) is geographically separated from the pancreas. Upon reaching the duodenum, trypsinogen is activated by en terokinase and trypsin activates the other digestive enzyme zymogens. What are the initiators of the premature activation of zymogens to active en zymes within the pancreas? There is good reason to believe that in addition to a special etiological mechanism some cofactors are needed to initiate actual de struction of the pancreas and peripancreatic tissues (Tables 1,2). Some of the pro posed mechanisms of pancreatic injury include: intrapancreatic reflux of bile or duodenal contents, direct disruption of the pancreatic parenchyma or duct, ob struction of pancreatic ducts, altered pancreatic ductal permeability, ischemia, al- Table 1. Etiological factors in pancreatitis. (Adapted from Schmidt and Creutzfeld [20]) I. Diseases of adjacent organs a) Biliary tract disease b) Duodenal disorders 2. Obstruction of pancreatic ducts 3. Alcoholism 4. Vascular disease 5. Infections 6. Endocrine and metabolic disorders 7. Nervous factors 8. Allergy 9. Drugs, toxins 10. Hereditary pancreatitis 11. Trauma, operation Table 2. Some initiators of acute pancreatitis. (Modified from Ranson [17]) Parenchymal or ductal disruption Obstruction of pancreatic duct or lymphatics Altered pancreatic ductal permeability Reflux of bile and/or duodenal contents Ischemia Altered acinar cell stability Role of Pancreatic Enzymes in Acute Pancreatitis 69 tered acinar cell stability, and activation of the complement system. However, ob jections have been made as to the significance of each of these factors. The mechanisms which most often have been incriminated in the initiation of pancreatic necrosis are reflux of duodenal contents and of bile into the pancreatic ducts. Reflux of duodenal contents (containing activated pancreatic enzymes, en terokinase, bile, and lecithin) and bile into the pancreatic ducts leads to the gen eration of bile acid monomers due to breakdown of micelles and of lysolecithin. These cytotoxic products initiate a positive feedback cycle of disruption of duct permeability, activation of enzymes, and acinar cell necrosis [13]. Recent studies in dogs [8, 16] have shown that transient pressure gradients occur across the pan creatic duct sphincter of dogs which might favor reflux into the pancreatic duct without causing pancreatitis. Thus, reflux of bile and of duodenal content into the pancreatic duct may be a physiological event and unknown additional factors may be needed for initiating acute pancreatitis. How are the individual enzymes activated and what happens when they are activated? We cannot answer this question definitely since our knowledge is mainly derived from animal studies, but there are some good reasons to believe that the human pancreas acts in a similar way. A number of experimental models of pancreatitis have been developed (Table 3). From these studies we know that the critical ingredient must include disruption of acinar or ductal integrity, egress of pancreatic secretion into tissue spaces, and activation of the enzymes. The similarity of experimental pancreatitis to the human disease is, obviously, always open to question, and the issue of how digestive enzymes become activated within the pancreas during clinical pancreati tis remains both critical and unresolved. Mainly recent studies [2, 10, 12] in which noninvasive methods of inducing experimental pancreatitis have been used have provided some insight into the events which may occur during the early stages of pancreatitis. For example, studies in mice, in which a choline-deficient ethionine supplemented diet was given to induce pancreatitis, have shown that in diet-in duced pancreatitis, digestive enzyme secretion is blocked, zymogen granules accu mulate, and zymogen granules fuse with lysosomes by a process known as crino phagy [7, 11]. As a result digestive enzymes and lysosomal hydrolases are exposed to each other and the known ability oflysosomal enzymes to activate trypsinogen may explain the intrapancreatic activation of digestive enzymes observed in this Table 3. Some models of experimental pancreatitis. (Adapted from Steer and Meldolesi [21)) Invasive models Retrograde ductal injection Intraparenchymal injection Closed duodenal loop Duct ligation and stimulation of secretion Noninvasive models Anticholinesterase insecticide Hyperstimulating doses of secretagogues Choline-deficient ethionine-supplemented diet 70 M. V. Singer et al. model of pancreatitis. Adler and Kern [1] concluded from their data obtained from six patients who died from acute pancreatitis that the heavy involvement of lysosomes in the autophagic removal of secretory product and cellular organelles is a mechanism which rids the cell of unused secretory proteins and altered in tracellular structures. In certain cases this process leads to cellular necrosis while in other cases it leads only to the progressive removal of distal secretory compart ments from the exocrine cell. Trypsin It is probably trypsin that plays a key role in the pathogenesis of acute pancreati tis. This enzyme is able to activate the majority of proenzymes taking part in the process of autodigestion, such as trypsinogen (by autocatalysis), proelastase, pro phospholipase A, and kallikrein [20]. Traces of trypsin or chymotrypsin activity have been detected in human pancreatic juice or ascitic fluid in acute pancreatitis [3,6]. In experimental studies, significant amounts of trypsin, chymotrypsin, and elastase were found in pancreatic tissue in the early phase of the disease [18]. It is therefore thought that the activation of trypsinogen is the important triggering event in acute pancreatitis [9]. There is some indication that under certain circumstances only traces of active trypsin which may not be detected with enzymatic methods and which are rapidly inactivated by inhibitors of pancreatic tissue or plasma are sufficient to give ac tivation of other pancreatic zymogens and to trigger the cascade of autodigestion known as acute pancreatitis. As mentioned above, this may occur when cell injury or necrosis results from a variety of causes. Trypsin may autocatalyze its own ac tivation,

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