7 : 14. Deepak Kumar Bhasin, Surinder Singh Rana, Chandigarh. Etiology

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1 7 : 14 Acute Pancreatitis: Pathogenesis, Diagnosis and Management Other Than Nutrition Acute pancreatitis (AP) is an acute inflammation of the pancreatic gland and surrounding tissues. It is a potentially life threatening disease with significant morbidity and mortality and includes a wide spectrum of disease, ranging from mild pancreatitis alone, to severe cases of extensive pancreatic necrosis with multiorgan failure in which mortality rates can reach 20% to 30% or higher systemic inflammatory response syndrome (SIRS) accounts for early mortality. Later mortality is usually caused by infection and sepsis. It is important to correctly diagnose and manage appropriately this potentially serious condition in order to reduce the morbidity and mortality. This article reviews clinical management of acute pancreatitis including the pathophysiology, diagnosis, and therapy excluding the nutritional aspect. Etiology There are many causes of acute pancreatitis with alcohol and gallstones being responsible for majority of the cases. The other causes of acute pancreatitis have been listed in table 1. Table 1: Causes of acute pancreatitis Gallstones (including microlithiasis) Alcohol Hypertriglyceridemia Post endoscopic retrograde cholangiopancreatography (ERCP) Trauma Postoperative (abdominal and non abdominal operations) Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, anti-hiv medications) Sphincter of Oddi dysfunction Vascular causes and vasculitis Connective tissue disorders Pancreatic carcinoma Hypercalcemia and hyperparathyroidism Pancreas divisum and other congenital ductal anomalies of pancreas Anomalous pancreaticobiliary ductal junction Hereditary pancreatitis and other genetic causes Cystic fibrosis Renal failure Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites) Autoimmune (e.g., Sjögren s syndrome) Posterior penetrating ulcer Idiopathic Deepak Kumar Bhasin, Surinder Singh Rana, Chandigarh The mechanisms by which these conditions trigger pancreatic inflammation have not been clearly identified. Gallstones or alcoholism causes about 75% of all cases of acute pancreatitis. With thorough diagnostic evaluation, the cause of pancreatitis can be identified in approximately another 10% of cases and the rest 15% cases are labeled as idiopathic acute pancreatitis. However, with advancement in genetics, we would probably be able to define the mystery of these remaining cases of idiopathic acute pancreatitis. Pathogenesis The acute pancreatitis is triggered by intrapancreatic digestive pancreatic enzyme activation and acinar cell injury. Some of the pancreatic enzymes, such as amylase, lipase, DNAase, and RNAase are secreted as active enzymes, but others, including most of the digestive enzymes (eg, trypsin, chymotrypsin, phospholipase, elastase, and carboxypeptidase) are synthesized as inactive proenzymes or zymogens. The proenzymes are packaged in secretory granules that transport the enzymes to the apex of the acinar cell facing the lumen of the pancreatic duct to prevent premature activation inside the cell. Proteases then are excreted into the duct lumen by exocytosis of the zymogen granules and are activated only after they reach the gut lumen through the action of enteric enteropeptidases. Under normal physiological situations, small amounts of trypsinogen may get activated inside the pancreas, this is quickly considered by intrinsic defense mechanisms of pancreas which remove activated trypsin. These mechanisms include the secretion of the pancreatic secretory trypsin inhibitor (PSTI or SPINK1), which binds and inactivates about 20% of the trypsin activity. Another mechanism for inactivation is by means of the nonspecific anti proteases such as alpha-1-antitrypsin and alpha-2-macroglobulin. Pancreatic hyperstimulation or injury causes intracellular activation of pancreatic enzymes by localization of the lysosomal enzymes like cathepsin B with trypsinogen this lead to their activation or may lead to altered secretion of activated proteases or their

2 Acute Pancreatitis: Pathogenesis, Diagnosis and Management Other Than Nutrition Table 2: Acute Pancreatitis: Symptoms and Signs Abdominal pain 90 % Abdominal rigidity 80 % Nausea, vomiting 80 % Ileus 55 % Jaundice 30 % Shock 20 % Neurological symptoms 10 % Grey Turners, Cullen s signs 2-3 % proenzymes through the basolateral membranes of the acinar cells followed by their leakage into the interstitium circulating protease inhibitors are inactivated by oxygen radicals released following pancreatic injury this leads on to the accumulation of activated enzymes in pancreatic tissue. Continued presence of inciting stimulus leads to release of trypsin which in capacitates the normal defense mechanisms of the pancreas activates other enzymes such as phospholipase, chymotrypsin, and elastase and also activates other cascades, including complement, kallikrein kinin, coagulation, and fibrinolysis. The release of active pancreatic enzymes within the pancreatic tissue leads to pancreatic autodigestion which then release more active enzymes. The active enzymes digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal cell necrosis. Cellular injury and death result in the liberation of bradykinin peptides, vasoactive substances, histamine and inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor- a (TNF a) that produce vasodilatation, increased vascular permeability, and systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) as well as multiorgan failure. This profound inflammatory response produces most of the early morbidity and mortality in AP and the second, late-phase (> 2 weeks) is characterized by infectious complications of gland necrosis and the sequelae of organ failure. Diagnosis Abdominal pain is the most common and important symptom of AP and is observed in 90-95% of the patients (Table 2). Pain may vary from a mild and tolerable discomfort to severe and incapacitating pain. Typically it is generalized to the upper abdomen and occurs acutely, without a prodrome rapidly reaching maximum intensity. It tends to radiate to the back as well as to the chest, flanks, and lower abdomen and can last for several days. The pain typically is boring and deep because of the retroperitoneal location of the pancreas. The pain tends to be steady but is exacerbated by eating or drinking, and patients may lean forward or even curl up in a knee-to-chest to decrease the pain by decreasing the stretch on the pancreas. Patients may also have nausea and vomiting that is related to peripancreatic inflammation extending to the posterior gastric wall and a localized or generalized ileus. The severity of the physical findings depends upon the severity of an attack of AP. Physical examination frequently reveals a distressed and anxious patient. Mild disease presents with only mild abdominal tenderness. Severe disease presents with severe abdominal tenderness and guarding and sluggish bowel sounds, accompanied by epigastric distention. Tachycardia and hypotension may result from hypovolemia because of sequestration of fluid in the pancreatic bed. Patients may also develop low-grade fever because of peripancreatic inflammation and this does not denote active infection. Patients may have shallow, rapid respirations from diaphragmatic inflammation, pleural effusions, and respiratory compromise. Uncommon physical findings include: Subcutaneous fat necrosis, or panniculitis, that typically presenting as tender, palpable, subcutaneous, red nodules along the distal extremities. Ecchymoses in the flanks, called Gray-Turner s sign, indicate retroperitoneal hemorrhage from hemorrhagic pancreatitis, whereas ecchymoses in the periumbilical region, called Cullen s sign, indicate intra-abdominal hemorrhage. Jaundice suggests bile duct obstruction from gallstones or compression of the intrapancreatic portion of the common bile duct by the edematous head of pancreas or pancreatic fluid collection. Investigations Leukocytosis is common because of a systemic inflammatory response. Patients with more severe disease may show hemoconcentration with hematocrit values >44% as a result of loss of plasma into the retroperitoneal space and peritoneal cavity. Mild hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and an increased output of adrenal glucocorticoids and catecholamines. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels sometimes are mildly elevated in alcoholic pancreatitis but are significantly elevated in biliary pancreatitis. An ALT level threefold or more above normal suggests biliary rather than alcoholic pancreatitis. Hypocalcemia occurs in ~25% of patients, and its pathogenesis is not completely understood. Hypertriglyceridemia occurs in upto 20% of patients, and serum amylase and lipase levels in these individuals are often spuriously normal. Approximately 25% of patients have hypoxemia, which may precede the onset of ARDS. The electrocardiogram occasionally shows ST-segment and T-wave abnormalities simulating myocardial ischemia. Serum amylase The serum amylase level has been the traditional, standard diagnostic blood test for AP. The serum amylase level increases during acute pancreatitis from leakage from the inflamed pancreas into the bloodstream. Although serum amylase is a very sensitive diagnostic test, hyperamylasemia lacks specificity. Many disorders like macroamylasemia, renal failure, parotitis, esophageal perforation and pregnancy cause hyperamylasemia. The serum amylase level will be falsely normal or low values in following situations: when blood tested too early in delayed clinical presentation as the serum amylase normalizes after several days of pancreatitis; in pancreatitis resulting from hypertriglyceridemia, possibly because of the dilutional effects of the lipemia; and in acute-on-chronic alcoholic pancreatitis. 543

3 Medicine Update 2010 Vol. 20 Serum lipase and other serum markers The serum lipase level is an important diagnostic marker for acute pancreatitis because of high sensitivity and specificity. The serum lipase level rises early in pancreatitis and remains elevated for several days. It may also increase in renal failure as well as intestinal inflammation or perforation. CRP Other pancreatic enzymes that leak and accumulate in the serum include phospholipase A, trypsin, trypsinogen-2, and carboxyl ester lipase as well as proteins including pancreatitis-associated protein and trypsinogen activation peptide. These laboratory tests are experimental and are not used routinely for diagnosis because of the excellent sensitivity and specificity of the serum lipase test Radiological Investigations Abdominal contrast enhanced computed tomography (CECT) remains the cornerstone investigation for diagnosing and assessing the severity of AP. It can confirm the clinical impression of acute pancreatitis even when serum amylase levels are normal. Abdominal radiographs are performed mainly to exclude alternative abdominal diseases, such as gastrointestinal perforation but indirect finings suggesting AP may be visualized that include generalized ileus, presence of a sentinel loop because of spasm of distal bowel overlying the inflamed pancreas, colon cut-off sign, where the mid-transverse colon is dilated focally because of extension of peripancreatic inflammation and bowel spasm at the splenic flexure and widening of the C-loop of the duodenum. Chest X Ray may reveal pleural effusion or basal atelectasis. Ultrasound of the abdomen can demonstrate an edematous swollen pancreas with reasonable sensitivity when it can be visualized, but it is often obscured by gas-filled paralytic bowel loops or abdominal fat limits the penetration of ultrasound waves. Abdominal ultrasound is also less accurate than CECT in delineating peripancreatic inflammation and detecting pancreatic necrosis. It is, however, an excellent modality for detecting gall bladder stones. CECT of the abdomen is an important investigation for evaluation of a patient with suspected acute pancreatitis. It can help in confirming the suspected diagnosis of acute pancreatitis and also helpful in assessing for alternative causes for the acute abdominal pain that mimic acute pancreatitis, such as bowel perforation, ruptured aortic aneurysm, and mesenteric ischemia. Also, CECT is helpful in indicating the severity of acute pancreatitis and evaluating the complications of acute pancreatitis. In mild pancreatitis, on CECT the gland may appear normal. As the intensity of the inflammatory process increases, the pancreas becomes enlarged and the borders of the gland become indistinct, with hazy soft tissue stranding consistent with inflammation surrounding the pancreas. With increasing severity, the inflammatory stranding and fluid may extend away from the pancreas. Pancreatic necrosis appears as zones of low attenuation representing non-enhancing parenchyma or as fluid-filled areas replacing the pancreatic parenchyma. CECT abdomen has a good safety profile in patients with AP and normal renal function. Initially, concerns were raised regarding worsening of pancreatic necrosis by administration of intravenous contrast were raised, as documented in an animal model. However, this has not been corroborates in other animal models nor been demonstrated clinically and contrast administration is considered safe in AP. Magnetic resonance imaging (MRI) is sensitive and can depict the findings as seen on CT. It also offers advantage of evaluation of the biliary system and gallbladder. However, it has limited application in acute pancreatitis because it has limited availability, is more cumbersome and is difficult to perform in the setting of AP. In spite of this, it has advantages in situations, like pregnancy, allergy to contrast used in CT, and renal failure. Endoscopic ultrasound is also an important investigation for detecting choledocholithiasis and can also be used in pregnancy but the logistics of performing it in AP limits its routine use. Assessing Disease Severity It is important to assess the severity of AP in order to recognize the pancreatic complications at an early stage and also for proper triage of patients and assessing the prognosis. The biochemical markers like amylase and lipase correlate poorly with severity. The clinical impression, based on evaluation of the vital signs, respiratory distress, renal insufficiency, other evidence of organ failure, and abnormal laboratory tests, is fairly specific but relatively insensitive in determining disease severity and predicting complications. Leukocytosis, elevated C-reactive protein, procalcitonin, polymorphonuclear leukocyte elastase, TNF a, IL-1b, ghrelin, leptin and trypsinogen activation peptide suggests a severe disease. Formal clinical scoring systems improve the accuracy of determining disease severity. Multiple factor scoring systems like Ranson, Imrie and APACHE II have been developed but are difficult to use and have poor predictive powers. The Ranson criteria differentiate between mild and severe pancreatitis with about 80% accuracy, but require evaluation of 11 parameters over 48 hours. The APACHE II scale has advantages in that it can be performed on admission, can be reevaluated at any time, and is applicable to any illness. It incorporates 11 physiologic variables in addition to the patient s age, organ insufficiency, neurological status and postoperative state. It is a fairly reliable indicator of disease severity and predictor of complications but cumbersome to use clinically. Importantly, the key indicators of a severe attack of pancreatitis are age > 70 years, body mass index (BMI) > 30, hematocrit > 44%, and admission C-reactive protein > 150 mg/l, respiratory failure (P O2 < 60 mmhg), shock (systolic blood pressure < 90 mmhg or tachycardia > 130), renal failure [serum creatinine > 2.0 mg/dl)], and gastrointestinal bleeding (>500 ml/24 h). CECT is an important radiological investigation for diagnosing 544

4 Acute Pancreatitis: Pathogenesis, Diagnosis and Management Other Than Nutrition Table 3: CT severity Index Grade Findings Score A Normal Pancreas 0 B Pancreatic enlargement 1 C Pancreatic or peripancreatic fat inflammation 2 D Single peripancreatic fluid collection 3 E Two or more fluid collections or retroperitoneal air 4 No pancreatic necrosis 0 additional points < 30%pancreatic necrosis 2 additional points 30-50% pancreatic necrosis 4 additional points > 50% pancreatic necrosis 6 additional points pancreatic necrosis and thus assessing the disease severity. The CT severity index includes findings of inflammation with noncontrast CT and findings of necrosis with contrast CT (table 3). It has a sensitivity of 85% and a specificity of 98% in predicting severe pancreatitis based. Patients who had a CT severity index greater than five were found to be eight times more likely to die, 17 times more likely to have a prolonged hospital course, and 10 times more likely to require necrosectomy than patients who had a severity index less than five. Management Early management The management of acute pancreatitis requires a team approach involving gastroenterologist, surgeon, radiologist and intensive care physician. Patients having early signs of organ failure should be monitored in an intensive care unit (ICU). The goals of therapy for acute pancreatitis are general supportive therapy to prevent complications, directed therapy for specific causes of pancreatitis, and early recognition and aggressive treatment of complications. In most patients (85 90%) with acute pancreatitis, the disease is self-limited patients improves usually within 3 7 days after treatment is instituted. The treatment includes analgesics for pain and intravenous fluids and colloids to maintain normal intra vascular volume. It is important to treat aggressively severe necrotizing pancreatitis. Initial management of necrotizing pancreatitis is focused for maintenance of adequate intra vascular volume and end organ perfusion in the face of the systemic inflammatory response, capillary leak and peripancreatic inflammation causing substantial extravasation of fluid in the third space. All the patients should be monitored closely for assessment of intra vascular volume and adequacy of organ perfusion by frequent physical examination and evaluation of vital signs for tachycardia or hypotension, monitoring of hourly urine output, and frequent analysis of serum acid base status and oxygenation by arterial blood gas. In with concomitant cardiovascular disease invasive monitoring of central venous and pulmonary wedge pressures with a Swann-Ganz catheter should be done for assessing adequate rehydration. In addition to crystalloid resuscitation, patients with necrotizing pancreatitis should not be fed orally to reduce pancreatic stimulation. If there are signs of gastric ileus and distension, a nasogastric tube should be placed for gastric decompression. Most patients should receive stress ulcer prophylaxis and deep vein thrombosis prophylaxis with subcutaneous low molecular weight or unfractionated heparin unless contraindicated. Numerous additional pancreatitis-specific therapies have been investigated, including the use of pharmacologic agents targeting various components of the inflammatory cascade like trypsin inhibitor aprotinin, a platelet-activating factor inhibitor lexipafant, the protease inhibitor gabexate mesylate, and octreotide for pancreatic suppression have been evaluated with not so encouraging results. An additional therapeutic area is the optimal delivery of nutritional support to these patients, which will not be discussed in this review. Along with nutrition, the role of hyperglycemia is also important and it has been shown that using insulin therapy to achieve mean blood glucose of less than 110 mg/dl reduces mortality by 3% to 4%. Hypocalcemia commonly occurs with acute pancreatitis, particularly when the attack is severe. Serum calcium levels should be carefully monitored. The arterial oxygen saturation should be maintained at > 95%, with supplemental oxygen administered by nasal cannula or facemask as necessary. Endotracheal intubation and assisted ventilation should be performed early i) if the patient remains hypoxic despite these measures, ii) has severe pulmonary disease, or iii) has respiratory fatigue. Hypoxemia in the absence of pre-existing pulmonary disease may be an early sign of the adult respiratory distress syndrome (ARDS) and patient may need endotracheal intubation and mechanically assisted ventilation using high positive end-expiratory pressures. Infection occurs in 20% to 40% of patients with necrotizing pancreatitis and a number of small-randomized prospective studies have suggested possible benefit to prophylactic antibiotic administration in patients with evidence of pancreatic necrosis. Appropriate antibiotic therapy must demonstrate both penetration of pancreatic tissue and coverage of the expected infectious flora and carbapenems, quinolones, and nitroimidazoles fit in this profile. The benefit of antibiotic prophylaxis, however, in the treatment of necrotizing acute pancreatitis remains controversial. After initial encouraging results, two large, placebo-controlled, double blind trials have failed to show a benefit to prophylaxis with regard to either infection rates or mortality. A recent metaanalysis also, published in 2009 has shown that antibiotic prophylaxis is not effective in acute severe pancreatitis. In early stage of necrotizing pancreatitis is treated by aggressive resuscitation and intensive support. The role of surgery during this period is limited. Earlier, there has been increased enthusiasm for early surgical intervention in the setting of extensive pancreatic necrosis, but increased mortality with early intervention, has shifted the management form aggressive surgery to intensive care management. Early endoscopic retrograde cholangiography has been shown to improve outcome in subset of patients with gall stone pancreatitis and a persistently impacted common bile duct stone. Most current guidelines recommend ERCP when biliary obstruction or cholangitis are present. 545

5 Medicine Update 2010 Vol. 20 Late Management The late phase of severe pancreatitis is characterized by infectious or hemorrhagic complications. Without surgical management the mortality in the setting of infection approaches 100%, whereas with surgical management the mortality is ~ 25%. Other indications for intervention include the drainage-debridement of persistent symptomatic fluid collections, and prolonged failure-to-progress with ongoing organ dysfunction in the absence of documented infection. Hemorrhage is a rare complication of severe pancreatitis and is usually managed with angiography and embolization. Angiography is 96% sensitive in identifying the source of hemorrhage, and embolization is feasible and successfully controls hemorrhage in approximately 60% of patients. Surgical management is done in cases of failure of embolization to control bleeding. Infected necrosis has generally to be managed with immediate surgery. However recently, a trend has been developing toward conservative management even of patients with infected necrosis, provided that there are no signs of sepsis and organ failure. Even when it has been decided to intervene, there is a tendency to postpone intervention so as the necrosis organizes and this facilitates necrosectomy. So-called walled-off pancreatic necrosis (WOPN) can be removed far more easily, and the chance of bleeding or bowel perforation is reduced, as is the chance of intraabdominal spread of infection. Several intervention strategies for infected necrosis have been developed over a period of time. These include 1) open necrosectomy, 2) minimally invasive retroperitoneal necrosectomy, 3) percutaneous drainage, and 4) endoscopic necrosectomy. Of these, there is a lot of work being done on endoscopic necrosectomy. The details of these techniques are not being discussed in this article. References 1. Cappell MS. Acute Pancreatitis: Etiology, Clinical Presentation, Diagnosis, and Therapy. Med Clin N Am 2008: 92: Toouli J, Brooke-SmithM, Bassi C, et al. Guidelines for the management of acute pancreatitis. J Gastroenterol Hepatol 2002;17(Suppl):s Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990;174: Gurleyik G, Emir S, Kilicoglu G, et al. Computed tomography severity index, APACHE II score, serum CRP concentration for predicting the severity of acute pancreatitis. JOP 2005; 6: Papachristou GI, Clermont G, Sharma A, et al. Risk and markers of severe acute pancreatitis. Gastroenterol Clin North Am 2007;36: Golub R, Siddiqi F, Pohl D. Role of antibiotics in acute pancreatitis: a meta-analysis. J Gastrointest Surg 1998;2: Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101: Fosmark CE, Baillie J. AGA Institute technical review on acute pancreatitis. Gastroenterology 2007;132: de Vries AC, Besselink MG, Buskens E, et al.: Randomized controlled trials of antibiotic prophylaxis in severe acute pancreatitis: relationship between methodological quality and outcome. Pancreatology 2007, 7: Besselink MG, Verwer TJ, Schoenmaeckers EJ, et al.: Timing of surgical intervention in necrotizing pancreatitis. Arch Surg 2007, 142: van Santvoort HC, Bollen TL, Besselink MG, et al.: Describing peripancreatic collections in severe acute pancreatitis using morphologic terms: an international interobserver agreement study. Pancreatology 2008; 8: Schrover IM, Weusten BL, Besselink MG, et al.: EUS guided endoscopic transgastric necrosectomy in patients with infected necrosis in acute pancreatitis. Pancreatology 2008, 8: Villatoro E, Bassi C, Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev 2006;(4): CD Heinrich S, Schafer M, Rousson V, et al. Evidence-based treatment of acute pancreatitis: a look at established paradigms. Ann Surg 2006;243: Fan ST, Lai EC, Mok FP, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 1993;328: Mier J, Leon EL, Castillo A, et al. Early versus late necrosectomy in severe necrotizing pancreatitis. Am J Surg 1997;173: Muddana V, Whitcomb DC, Papachristou GI. Current management and novel insights in acute pancreatitis. Expert Rev Gastroenterol Hepatol ;3: Rickes S, Uhle C. Advances in the diagnosis of acute pancreatitis. Postgrad Med J ;85: Bakker OJ, van Santvoort HC, Besselink MG, van der Harst E, Hofker HS, Gooszen HG; Dutch Pancreatitis Study Group. Prevention, detection, and management of infected necrosis in severe acute pancreatitis. Curr Gastroenterol Rep ;11: