Acute pancreatitis is a common disorder that results from acute inflamatory injury of the pancreas.The clinical picture ranges from mild disease to multiorgan failure and sepsis, specially in the severe necrotizing or hemorragic forms of disease. And although the diagnosis is not a major concern, the treatment has been largely empirical since the mechanims by which the well recognized etiological factors lead to the development of the disease remains to be stablished.In others words, the actual sequence of events resulting in disease causation and evolution are not well known and, as a consequence, the results of the current therapeutic approaches are disappointing. For this reason, strong efforts have been made to elucidate the pathophysiology of acute pancreatitis, since this will lead to the development of better remedies and perhaps to the early recognition of local and systemic complications, with a lower mortality rate and better outcome to our patients.
The main goal of this article is to summarize the current concepts about the etiology of acute pancreatitis, and how these agressive factors lead to pancreatic tissue damage and systemic involvement that is typical of this disease.
Etiology
There are lots of causes known to produce acute pancretitis. Gallstones are the most common cause accounting for 45% of cases in Western Europe, Asia and United States. Other obstrutive causes of pancreatitis are uncommon like pancreas divisum, pancreatic carcinoma and metastatic cancer. Ascariasis is common cause of acute pancreatitis in children of developping countries, resulting from migration of worms into the biliary tree and pancreatic duct. Recently, hypertensive sphincter of oddi has been recognized as an important cause of the disease, and the search for this abnormality has reduced the number of cases previously taught to have idiophatic acute pancreatitis.
Alcohol is the second leading cause of acute pancreatis, although some experts do not believe that alcohol induces the disease but simply an acute attack in a previous silent cronic pancreatitis, based on histopathology and other evidences. More than 85 drugs have been described to cause pancretitis, the most common being azathioprine, mercaptopurine, DDI, valproic acid, estrogens, thiazides, furosemide, metronidazole, pentamidine, sulfonamides and tetracyclines. Also scorpion venom and organophosphorous inseticides have been implicated.
Traumatic causes of disease include blunt abdominal trauma, iatrogenic pancreatitis resulting from ERCP, specially in the case of endoscopical sphincterotomy, and after thoracic surgery, mainly after cardiopulmonary bypass, risk factors being hypoperfusion of pancreatic tissue and hypercalcemia due to the injection of calcium chloride. Hypertrigliceridemia and hypercalcemia are important causes of acute pancreatitis, as are infectious diseases produced by viral, bacterial and parasitic agents. Among these, the viral agents are the most common etiology, including mumps, coxsackie virus, hepatitis A, B, non-A, non-B, and cytomegalovirus.
The incidence of acute pancreatitis is higher in patients with AIDS than in the general population. It is probably due to the various opportunistic infections that can affect the pancreas like cryptococcus, cytomegalovirus, toxoplasma gondii, cryptosporidium and mycobacterium species, and the use of several "toxic" medications( DDI, pentamidine, etc).
Finally, other rare causes of the disease are penetrating peptic ulcer and Crohn`s disease of the duodenum. However, in spite of the plenty of etiologies enumerated in this review still the idiopathic causes being the third more common in most of the series. As we have seen, hypertensive sphincter of oddi or microlithiasis may be responsible for some of these cases.
Phatophisiology
The pathogenesis of acute pancreatitis remains poorly understood. In experimental models of disease numerous factors can initiate the process, including obstruction, exposure to ethanol and other toxins, hypetrigliceridemia, hypercalcemia, an increase in permeability of the pancreatic duct and hyperestimulation of the gland. However, how these factors initiate the celular disturbances that lead to acute pancratitis has not been elucidated. The intraacinar ativaction of trypsin from trypsinogen is believed to be one of the initiating events, common to most of the agressive factors. In fact, experimental models show a coalescence of zymogen granules with lysosome vacuoles, resulting in intrapancreatic activation of proteolytic enzymes. Small amounts of tripsin can be countered by endogenous pancreatic tripsin inhibitor. But, large amounts of tripsin release can overwhelm the serological defense mechanims( alfa-1-antitrypsin and alfa-2-macroglobulin), activate other enzimes, resulting in the local and systemic complications commonly seen in the course of the disease.
In this picture, the activaction of the enzyme phospolipase A2 has important consequences like the destruction of pulmonary surfactant that can result in ARDS, and the liberation of protaglandins and leucotriens that may be important in the pathogenesis of systemic inflamatory response that occurs and can lead to multiorgan failure. More than that, inflamatory mediators may be used as predictors of disease severity in a near future, as will be discussed later in this section. Also the trypsin activates complement , kinin and kallikrein, possibly playing a part in disseminated intravascular coagulation, shock, renal failure and vascular instability .
The liberation of elastase promotes the digestion of the elastic components of pancreatic vessels leading to intrapancreatic hemorrhage, while the presence of lipase in the peripancreatic tissue results in fat necrosis. The necrotic pancreas may become secondarily infected by gram-negative bacteria translocated from the alimetary tract, with high mortality rate.
The alcohol, as demonstrated in experimental models, is capable of causing intracelular derangements, alterations in the intrapancreatic duct permeability, and precipitation of proteins. Since many of the patients tought to have alcoholic acute pancreatitis have histophatological features of cronic pancreatitis and the majority of then will develop chronic pancreatitis after the acute episode, still many experts do not believe in the existence of this entity.
Based on the pathogenic mechanisms discussed, many therapeutic approaches have been developed. Numerous clinical trials have tried to block pancreatic secretion, thus eliminating the participation of pancreatic enzimes in the pathophisiology. However, the use of glucagon, atropin, somatostatin, aprotinin, nasograstic suction among others, has not significantly modified the clinical course or the duration of the disease. Also the use of peritoneal lavage to remove toxins and fresh frozen plasma to restore the antiprotease system has not shown satisfatory results, showing that much remains to be stablished in the phatogenesis of this important disease.
One of the most important unsolved matters in the pathogenesis of acute pancreatitis is that even tough the pathophysiological events seen to follow a similar pattern regardless of the cause, the factors that determine disease severity remain poorly understood. The development of prognostic schemes is very important in order to early recognize those patients with a high risk of complications. Serum markers have been used with this purposal since the appearence of Ranson`s criteria. However, these variables are measured during the first 48 hours of admission. And this 48 hours delay may be the critical period in which prudent clinical manegement might improve outcome. So efforts must be made to indentify early predictors of disease severity, able to be evaluated in patient`s admission.
Recently, as the role of inflamatory response and oxidative stress in the pathogenesis of acute pancreatitis emerge, inflamatory markers have been proposed as better predictors of disease severity. The most promising of these are C-reative protein, interleukin-6, polymorphonuclear elastase, and, in urine, albumin, imunoglobulin G, trypsinogen activation peptide. Maybe new therapeutic approaches to the disease complications will be trough manipulation of these mediators. It is our hope that as the pathophysiology of the acute pancreatitis becomes more clear early recognition of the disease`s complications and their treament will be the imediate consequences. For a while, we should concentrate our efforts in disease prevention, a more efficient and low cost strategy.
If you want to know more about this subject try reading some of the references below, that have been the suport of this article:
1.Steinberg,W.;Tenner,S.:Acute Pancreatitis. New England Journal of Medicine 1994 Apr 28; 330(17):1198-210.
2.Banerjee, A.K.; Galloway, S.W.; Kingsnorth, A.N.: Experimental models of acute pancreatitis. British Journal of Surgery 1994 Aug; 81(8):1093-106.
3.Formela, L.J.; Galloway, S.W.; Kingsnorth, A.N.: Inflamatory mediators in acute pancreatitis. British Journal of Surgery 1995 Jan; 82(1):6-13.
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