34 Acute pancreatitis is a clinical syndrome characterized by abdominal pain and elevated pancreatic enzymes. The clinical and pathologic findings were first de- scribed in 1889. However, the diagnosis still remains quite elusive despite the availability of numerous labo- ratory and radiographic tests. The fact that autopsy studies continue to show a 30–42% incidence of undi- agnosed pancreatitis underscores the complexity in the diagnosis of acute pancreatitis. History and physical examination Abdominal pain is the most prominent feature of acute pancreatitis, occurring in approximately 95% of pa- tients. Pancreatitis has been documented without pain in association with Legionnaires’ disease, insecticide, postoperative states, and dialysis. The pain is usually in the epigastric and periumbilical area of the abdomen, with radiation to the back in 50% of cases. Occa- sionally, the pain is diffuse or radiates to the lower abdomen. Rarely, the pain radiates to the chest. The onset is frequently acute and reaches maximum inten- sity within 30–60 min. The pain is often very severe, boring in character, and constant in duration. Patients often describe an inability to get comfortable and consequently may appear restless. Rarely, the pain is ameliorated by hunching forward, which frees the retroperitoneal space. Significant doses of narcotics are usually required for adequate pain control. Nausea and vomiting occurs in a majority of patients and may require the insertion of a nasogastric tube for relief. Other diseases to consider in the differential diag- nosis of acute pancreatitis include inferior wall myocardial infarction, peptic ulcer disease (including gastric or duodenal perforation), intestinal ischemia or infarction, intestinal strangulation or obstruction, biliary colic, cholecystitis, appendicitis, diverticulitis, dissecting aortic aneurysm, ovarian torsion, or ectopic pregnancy. Many of these diseases are surgical or medical emergencies and need to be ruled out quickly. Perforations often result in acute diffuse abdominal pain and peritoneal signs, such as a rigid abdomen and rebound tenderness. Pain associated with pancre- atitis is usually localized to the upper abdomen and associated with less abdominal rigidity. Pain due to biliary colic and acute cholecystitis can be localized to the right upper quadrant of the abdomen but often is centered in the epigastric area similar to pain of pancreatitis. An abdominal ultrasound can identify choledocholithiasis and cholecystitis. Intestinal ob- struction may cause crescendo–decrescendo pain with significant abdominal distension and, occasionally, feculent vomiting as well. Intestinal ischemia and in- farction have variable degrees of pain, but often it is out of proportion to the physical examination and more gradual in onset than pancreatitis pain. Appendicitis can usually be distinguished by its history and location of pain. In cases of mild pancreatitis, patients may appear uncomfortable but not seriously ill, and the vital signs may be normal. However, in cases of severe pancreati- tis, patients may appear toxic and quite ill. In these pa- tients, hypotension and tachycardia may be present due to dehydration and severe pain. Low-grade fever is pre- sent in up to 60% of patients with pancreatitis. At the time of admission, high-grade fevers may be an indica- tor of cholangitis in the appropriate clinical setting. 4 How should acute pancreatitis be diagnosed in clinical practice? Richard S. Kwon and Peter A. Banks Tachypnea may be evident due to pain, fever, or pulmonary involvement. Findings on physical examination can be variable as well. Jaundice may be evident in those patients with acute biliary pancreatitis. Cardiac examination may reveal tachycardia. Pulmonary examination may reveal shallow breathing due to diaphragmatic irrita- tion from pancreatic inflammatory exudate and ab- dominal pain. Auscultation and percussion of the lungs may reveal signs of a pleural effusion, which is usually on the left pleural space or bilateral, and only rarely confined to the right. Abdominal examination gener- ally reveals distension and tenderness, particularly in the epigastrium. Patients with mild pancreatitis describe pain that is moderate but strong enough to re- quire evaluation. However, patients with severe pan- creatitis may have exquisite tenderness and even a rigid abdomen that appears to be a surgical abdomen. Bowel sounds are often hypoactive due to ileus. Ecchymosis in the flanks (Grey Turner’s sign) or near the umbilicus (Cullen’s sign) can arise from local extravasation of pancreatic exudate. These two physical findings, while present in only 3% of cases of acute pancreatitis, are associated with 35% mortality. Other findings on physical examintion can be quite useful. For instance, a general eye examination can be occasionally helpful in determining the etiology of pancreatitis. An arcus lipoides implicates hypertrigyl- ceridemia. Band keratopathy suggests hypercalcemia. Rarely, Purtscher’s retinopathy causes visual distur- bances. Skin examination may reveal subcutaneous fat necrosis (panniculitis) over the distal extremities and rarely the trunk, buttock, or scalp. Polyarthritis has been described as well. Laboratory evaluation Serum and urinary tests can support the diagnosis of acute pancreatitis and may also help in the determina- tion of its etiology. Radiologic findings can confirm the diagnosis. Amylase Pancreatic amylase (1,4-a- D-glucan glucanohydrolase) is an enzyme derived from acinar cells that hydrolyzes internal a-1,4 linkages in complex carbohydrates. In acute pancreatitis, amylase secretion into pancreatic juice is impaired, resulting in extravasation from the gland and reabsorption into the systemic circulation via venules or lymphatics. Serum levels rise within 2 hours, peak in the first 48 hours, and can return to nor- mal in 3–5 days via renal and extrarenal mechanisms. Its rapid clearance and short half-life underscore the importance of determining the amylase concentration early in the course of the disease before the serum levels return to normal. Of note, the serum concentration does not correlate with either etiology or severity. Total serum amylase concentration is generally con- sidered the gold standard for diagnosing acute pancre- atitis; however, there are several limitations to this test. In an analysis of studies determining the diagnostic accuracy of serum amylase, the sensitivity was found to be only 83% and to be particularly limited in three situations. 1 If it is determined several days after the onset of symptoms, the serum amylase concentration may have already normalized. 2 Concomitant hypertriglyceridemia can result in a normal amylase level possibly via an inhibitor, which can be negated by serial dilution. 3 In chronic acinar cell damage, for example as a result of chronic alcoholic pancreatitis, the pancreas may not be able to produce sufficient amylase during a bout of pancreatitis to be elevated. Ultimately, if the serum amylase is normal and there is sufficient clinical suspicion of acute pancreatitis, a serum lipase level or computed tomography (CT) should be obtained to confirm the diagnosis. An elevated amylase level does not always indicate pancreatitis (Table 4.1). There are numerous non- pancreatic sources of amylasemia, including salivary glands (which produce the most prevalent amylase iso- form), ovaries, and fallopian tubes. Diseases of these organs may cause hyperamylasemia in the absence of pancreatitis. The most common intraabdominal diseases that can result in hyperamylasemia include intestinal diseases such as perforated peptic ulcer, intestinal obstruction, or mesenteric infarction (likely from leakage of intraluminal amylase and subsequent peritoneal reabsorption), and biliary diseases such as cholecystitis. Other conditions that can cause nonpan- creatic hyperamylasemia include renal insufficiency (due to impaired clearance), acute alcohol intoxication (usually salivary amylase), diabetic ketoacidosis, liver metastases, head trauma, and lung cancer. An additional cause of hyperamylasemia is CHAPTER 4 35 macroamylasemia, an entity characterized by macro- molecular immunocomplexes of amylase bound to im- munoglobulins (usually IgA or IgG). These complexes are too large for glomerular filtration and result in chronically elevated levels of amylase. This benign condition may account for up to 28% of chronic unex- plained hyperamylasemia and should be considered when elevated serum amylase concentrations are found in conjunction with negligible urinary amylase levels. Because there are many nonpancreatic sources of hyperamylasemia, the specificity of serum amylase for diagnosing pancreatitis is only 88%. The specificity increases to greater than 90% when the cutoff for diag- nosis is two to three times normal. Measurement of amylase isoenzymes has been pro- posed as a way to clarify the significance of hyperamyl- asemia. Pancreatic amylase (p-isoamylase) normally comprises nearly 40% of total serum amylase, while salivary amylase makes up the remainder. In acute pan- creatitis, p-isoamylase rises to over three times normal. The sensitivity and specificity of p-isoamylase in diag- nosing acute pancreatitis was reported to be as high as 90 and 92%, respectively. However, elevated levels of p-isoamylase have been noted in renal insufficiency, in- testinal disorders such as perforation or ischemia, dia- betic ketoacidosis, and intracranial hemorrhage, and after endoscopic retrograde cholangiopancreatogra- phy (ERCP) or morphine administration. As a conse- quence, pancreatic isoenzymes are no more useful than total amylase and have no role in the diagnosis of acute pancreatitis. Amylase concentrations in urine are also elevated in acute pancreatitis due to enhanced renal clearance. A normal amylase/creatinine clearance ratio is ap- proximately 3% and rises to 6–10% or greater in acute pancreatitis. However, there have been case reports of acute pancreatitis with normal urinary clearances. The specificity of the test is limited by a number of nonpancreatic conditions that can elevate urinary clearance. These include severe burns, diabetic ketoacidosis, march hemoglobinuria, anorexia ner- vosa, and postoperative states. Furthermore, renal insufficiency tends to decrease creatinine clearance out of proportion to amylase clearance, which falsely ele- vates the ratio. Therefore, urinary clearance has no benefit over serum amylase levels in the diagnosis of acute pancreatitis. The role of the amylase/creatinine clearance ratio is to confirm the diagnosis of macro- amylasemia, which is characterized by a negligible concentration of urinary amylase and consequently a very low ratio. Lipase Pancreatic lipase (triacylglycerol acylhydrolase) is pro- duced by acinar cells and hydrolyzes glycerol esters of long-chain fatty acids. In acute pancreatitis, serum li- pase levels rise via the same mechanism as for amylase. PART I 36 Table 4.1 Causes of hyperamylasemia. (Adapted from Banks 1985.) Pancreatic disease Acute pancreatitis Complications of pancreatitis, e.g., pseudocyst, pancreatic ascites Pancreatic carcinoma Endoscopic retrograde cholangiopancreatography Gastrointestinal disease Biliary disease, e.g., cholecystitis Hepatitis/cirrhosis Intestinal perforation or trauma Intestinal ischemia or infarction Intestinal obstruction Acute appendicitis Acute diverticulitis Aortic aneurysm Acute gynecologic disease, e.g., salpingitis, ruptured ectopic pregnancy Ovarian cysts Salivary gland disease Mumps Calculous obstruction of salivary ducts Scorpion sting Effects of alcohol Tumors Papillary cystadenocarcinoma of ovary Carcinoma of lung Macroamylasemia Renal insufficiency Metabolic Diabetic ketoacidosis Anorexia nervosa Others Pneumonia Intracranial hemorrhage Prostate hypertrophy Drugs, including opiates Serum lipase rises 4–8 hours after the onset of symp- toms and peaks at 24 hours. Its half-life is longer than that of amylase and consequently lipase levels normal- ize more slowly (8–14 days). Thus, the principal advan- tage of lipase is its increased sensitivity in cases where there is a delay between the onset of symptoms and la- boratory evaluation, at which time amylase levels may have normalized. Serum lipase that is two to three times normal is generally thought to be more specific and sensitive (95% and 96% respectively) and to be more accurate than amylase, particularly at later dates in the course of the pancreatitis. Similar to hyperamylasemia, hyperlipasemia may not always signify pancreatitis. There are alternative sources of lipase, though fewer than for amylase. These include gastric lipase and a nonspecific hepatic triacylglyceride lipase. There are an increasing number of conditions associated with hyperlipasemia. Such intraabdominal diseases include intestinal pathology such as inflammatory bowel disorders, peptic ulcer disease, bowel perforation, small bowel obstruction or infarction, or abdominal trauma (all via the same mechanism as amylase), and hepatobiliary pathology such as hepatitis, biliary obstruction, and cholecystitis. Extraabdominal diseases include hypertriglyceri- demia, diabetic ketoacidosis, and renal insufficiency. In these cases, the lipase elevations are usually less than three times normal. Similar to macroamylasemia, macrolipasemia also appears to be a clinical entity, albeit rarer, and has been reported in association with Hodgkin’s lymphoma, Crohn’s disease, and sarcoidosis. Amylase and lipase Amylase has traditionally been the test of choice for di- agnosing acute pancreatitis, but given its higher sensi- tivity and specificity, lipase may actually be more valuable. However, many clinicians often check both serum amylase and lipase in the work-up of abdominal pain. The combination does not appear to improve ac- curacy. A diagnostic challenge arises when only one of the two levels is elevated. For example, amylase levels have been normal in up to 32% of patients with radio- graphically confirmed acute pancreatitis. These pa- tients were more likely to have alcoholic and/or chronic pancreatitis, a history of more frequent previous attacks, and a longer duration of symptoms before laboratory evaluation. In this situation, accurate diagnosis of acute pancreatitis can be made by ele- vated serum lipase concentrations or with radiologic tests. The lipase/amylase ratio has been proposed as a tool for establishing alcohol as the etiology of pancreatitis. Although some studies indicate that a ratio greater than 3 may be useful in distinguishing alcoholic pancreatitis from nonalcoholic pancreatitis, the ratio lacks sensitiv- ity and only identifies two-thirds of cases of alcoholic pancreatitis. Liver function tests Transaminases are used primarily to distinguish biliary pancreatitis from other causes of pancreatitis. A recent metaanalysis determined that a threefold or greater ele- vation of alanine aminotransferase (ALT) in the pres- ence of acute pancreatitis had a 95% positive predictive value for gallstone pancreatitis. However, it should be noted that only half of all patients with gallstone pan- creatitis have significant elevations of serum ALT, and therefore an ALT less than three times normal should not exclude the diagnosis. Other diagnostic tests Trypsinogen is a 25-kDa pancreatic protease that is secreted in pancreatic juice in two isoforms (trypsinogen-1 and trypsinogen-2). In acute pancreati- tis, trypsinogen-2 levels rise in both serum and urine over 10-fold. In two trials of approximately 500 patients, the sensitivity and specificity of a dipstick urine test to detect trypsinogen-2 were found to be 92–94% and 95–96%, respectively. The negative pre- dictive value was 99%; therefore, a negative test ruled out pancreatitis with high probability. The authors suggest that a negative test can quickly rule out pancre- atitis but a positive test merits further evaluation. Fur- ther validation of this test is needed. A test for serum trypsinogen-2 has also shown encouraging preliminary results. Serum immunoreactive trypsin, chymotrypsin, elas- tase, phospholipase A 2 , a 2 -macroglobulin, pancreatic activated protein, methemalbumin, carboxypepti- dases, and carboxyl ester hydrolase levels have been proposed for diagnosis of pancreatitis. They have been proven to be neither more accurate nor more beneficial than serum amylase or lipase and tests are not commer- cially available. CHAPTER 4 37 Radiology The primary role of radiology is to confirm the diagno- sis, to identify the possible cause of pancreatitis, and to assess the extent and complications. Ultrasound Abdominal ultrasound is generally not used to diag- nose pancreatitis. Its primary role is to rule out gall- stones as the etiology of pancreatitis and can also be used to preclude other diseases such as acute cholecysti- tis or hepatic abscesses. Visualization of the pancreas is often hindered by overlying bowel gas. Findings consis- tent with pancreatitis include diffuse glandular enlarge- ment, hypoechoic texture of the pancreas indicating interstitial edema, focal areas of hemorrhage or necro- sis within the pancreas, and free intraperitoneal fluid. Computed tomography Thin-section multidetector-row CT with intravenous contrast is the most important radiographic modality used to diagnose acute pancreatitis and to exclude other conditions causing abdominal pain, including mesenteric infarction and perforated duodenal ulcer. CT can also be used to determine severity of disease and to identify complications related to pancreatitis. Findings on CT that support the diagnosis of acute pancreatitis include diffuse edema and enlargement of the pancreas, heterogeneity of pancreatic parenchyma, peripancreatic stranding, obliteration of the peripan- creatic fat planes, and peripancreatic fluid collections. Pancreatic necrosis is defined as a focal or diffuse area of the nonenhanced pancreatic parenchyma following examination with intravenous contrast. In mild cases of pancreatitis, CT may be normal. Magnetic resonance imaging With evolving technology, particularly the develop- ment of magnetic resonance cholangiopancreatogra- phy (MRCP), magnetic resonance imaging has been increasingly used in the care of patients with pancreati- tis. MRCP can detect pancreatic necrosis and deter- mine severity as accurately as CT, and is superior in delineating pancreatic duct anatomy and detecting choledocholithiasis. In addition, potential nephrotoxi- city is minimized by the use of gadolinium contrast. Nonetheless, despite these benefits, CT can be obtained in a much more timely and cost-effective manner than MRCP in most hospitals and therefore remains the preferable radiologic test. Endoscopic retrograde cholangiopancreatography ERCP has no role in the diagnosis of acute pancreatitis. Its role is to treat choledocholithiasis and cholangitis and to delineate pancreatic ductal anatomy in cases of recurrent or unresolved pancreatitis. Endoscopic ultrasound Endoscopic ultrasound is an emerging technology in the care of pancreatic disease. However, its role in establishing the diagnosis of acute pancreatitis has not been established. Endoscopic ultrasound may serve as an alternate modality for detecting choledocholithiasis. Summary At present, a serum lipase level greater than three times normal appears to be the most accurate test for diag- nosing acute pancreatitis. Urinary trypsinogen-2 levels also accurately diagnose acute pancreatitis but a test is not yet commercially available. Thin-section multidetector-row CT with intravenous contrast is the study of choice to confirm the diagnosis. Recommended reading Balthazar EJ, Freeny PC, van Sonnenberg E. Imaging and intervention in acute pancreatitis. Radiology 1994;193: 297–306. Banks PA. Tests related to the pancreas. In: JE Berk (ed.) Bockus Gastronterology, 4th edn. Philadelphia: WB Saunders, 1985:427–444. Banks PA. Practice guidelines in acute pancreatitis. Am J Gastroenterol 1994;92:377–386. Chase CW, Barker DE, Russell WL et al. Serum amylase and lipase in the evaluation of acute abdominal pain. Ann Surg 1996;62:1028–1033. Dervenis C, Johnson CD, Bassi C et al. Diagnosis, objective as- sessment of severity and management of acute pancreatitis (Santorini Consensus Conference). Int J Pancreatol 1999; 25:195–210. PART I 38 Dominguez-Muñoz JE. Diagnosis of acute pancreatitis: any news or still amylase? In: M Buchler, E Uhl, H Friess, P Malfertheiner (eds) Acute Pancreatitis: Novel Concepts in Biology and Therapy. Oxford: Blackwell Science, 1999: 171–179. Elmas N. The role of diagnostic radiology in pancreatitis. Eur J Radiol 2001;38:120–132. Frank B, Gottlieb K. Amylase normal, lipase elevated: is it pancreatitis? A case series and review of the literature. Am J Gastroenterol 1999;94:463–469. Gullo L. Chronic nonpathological hyperamylasemia of pan- creatic origin. Gastroenterology 1996;110:1905–1908. Hedstrom J, Kemppainen E, Andersen J et al. A comparison of serum trypsinogen-2 and trypsin-2–a 1 -antitrypsin complex with lipase and amylase in the diagnosis and assessment of serverity in the early phase of acute pancreatitis. Am J Gastroenterol 2001;96:424–430. Keim V, Teich N, Fiedler F et al. A comparison of lipase and amylase in the diagnosis of acute pancreatitis in patients with abdominal pain. Pancreas 1998;16:45–49. Kemppainen EA, Hedstrom JI, Puolakkainen PA et al. Rapid measurement of urinary trypsinogen-2 as a screening test for acute pancreatitis. N Engl J Med 1997;336:1788–1793. Lankisch PG, Banks PA (eds) Pancreatitis. Berlin: Springer- Verlag, 1998. Lescesne R, Tourel P, Bret PM et al. Acute pancreatitis: inter- observer agreement and correlation of CT and MR cholan- giopancreatography with outcome. Radiology 1999;211: 727–735. Tenner S, Dubner H, Steinberg W. Predicting gallstone pancre- atitis with laboratory parameters: a meta-analysis. Am J Gastroenterol 1994;89:1863–1866. Toouli J, Brooke-Smith M, Bassi C et al. Working party report: guidelines for the management of acute pancreatitis. J Gas- troenterol Hepatol 2002;17(Suppl):S15–S39. Treacy J, Williams A, Bais R et al. Evaluation of amylase and lipase in the diagnosis of acute pancreatitis. Aust NZ J Surg 2001;71:577–582. Yadav D, Nair S, Norkus EP et al. Nonspecific hyperamyl- asemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol 2000;95:2123–2128. Yadav D, Agarwal N, Pitchumoni CS. A critical evaluation of laboratory tests in acute pancreatitis. Am J Gastroenterol 2002;97:1309–1318. CHAPTER 4 39 40 Acute pancreatitis is a frequent disease and one of the most frequent digestive disorders leading to hospital- ization in developed countries. The incidence of acute pancreatitis varies widely among different series, rang- ing from 5.4 to 79.8 cases per 100 000 inhabitants per year. Although it may be accepted that the incidence of the disease is to some extent lower in countries such as the UK and the Netherlands compared with the USA, Finland, or Spain, this geographic variability explains only partly the reported differences among series. The major difference is probably explained by the study de- sign, since the incidence of acute pancreatitis is much higher in prospective than in retrospective series. Dif- ferent criteria applied for the diagnosis of acute pancre- atitis most probably also play a role. Considering only prospective studies specifically designed to calculate the incidence of acute pancreatitis and that define the disease by the presence of acute abdominal pain and elevation of serum and/or urine levels of pancreatic enzymes at least twice the upper limit of normal, the incidence of acute pancreatitis ranges from 20 to 40 cases per 100 000 inhabitants per year. There is a peak of incidence between the fourth and sixth decades of life and no definite difference between males and females. Etiology of acute pancreatitis Several conditions are generally accepted as potential causes of acute pancreatitis (Table 5.1). Among these, gallstones and alcohol are responsible for more than 80% of episodes of the disease. Other causes are clearly less frequent, but their correct identification is highly relevant in order to apply the appropriate therapeutic measures to avoid relapses. Gallstones Common bile duct stones and sludge are well-known causes of acute pancreatitis. This is the most frequent etiologic factor associated with the disease in most countries. In addition, up to 75% of cases considered as idiopathic are related to biliary microlithiasis. Cholecystectomy and extraction of common bile duct stones prevent relapses of the disease, confirming the cause–effect relationship. Despite the close association between gallstones and acute pancreatitis, only a small percentage of patients with gallstones develop pancreatitis. In fact, the preva- lence of gallstones is as much as 12% in the general population. Thus, in an American study the risk of acute pancreatitis in the presence of gallstones has been estimated to be 12–35 times higher than in the general population. Two different studies in Spain provide a con- sistent odds ratio of 6.7 (95% confidence interval, 3.8– 11.8) for acute pancreatitis in the presence of gallstones. The mechanism by which gallstones induce acute pancreatitis is unknown. Most probably, transpapil- lary passage of a stone causes transient obstruction of both bile duct and pancreatic duct and this leads to acute pancreatitis. Consistent with this, small stones (diameter < 5 mm), which are more likely to pass from the gallbladder through the cystic duct, are more fre- quently associated with pancreatitis than large stones. Similarly, passage of microlithiasis through the papilla may cause pancreatitis by inducing ampullary edema and secondary obstruction. 5 Guidelines for the detection of the etiologic factor of acute pancreatitis J. Enrique Domínguez-Muñoz Alcohol Alcohol consumption is the second most frequent cause of acute pancreatitis in most countries. Although a di- rect relationship between the amount of alcohol intake and the risk of acute pancreatitis most probably exists, individual susceptibility to alcohol is variable. Thus, an alcohol consumption that may be considered socially normal is able to cause acute pancreatitis. It has been calculated that a mean daily consumption of 90 g alco- hol is required to match the risk of pancreatitis induced by gallstones. Acute excessive alcohol intake may cause acute pancreatitis in some patients, whereas chronic al- cohol consumption is most frequently associated with acute relapses of chronic pancreatitis. The diagnosis of underlying chronic pancreatitis in patients with acute alcoholic pancreatitis is often difficult. Endoscopic ultrasonography, because of its high sensitivity in the detection of early changes of chronic pancreatitis, may be of help in these situations. The exact mechanism of alcohol-induced acute pancreatic injury is unknown, although genetic and environmental factors are most probably involved. In addition, alcohol may act by increasing the synthesis of enzymes by acinar cells or by oversensitizing acini to cholecystokinin. Metabolic disorders Hypertriglyceridemia is a well-known cause of acute pancreatitis. Patients with hyperlipidemic pancreatitis often present with serum triglyceride levels above 1000 mg/dL. The serum is macroscopically opalescent due to increased chylomicron concentration. Hypertriglyceridemic pancreatitis may occur in pa- tients with types I and V hyperlipidemia as well as in al- coholics. Alcohol intake is one of the major factors inducing elevation of serum triglycerides. In fact, it is occasionally difficult to evaluate the potential role of hypertriglyceridemia in the origin of alcohol-related acute pancreatitis. Clinically, acute hyperlipidemic pancreatitis tends to be severe and up to 50% of patients present with necro- tizing pancreatitis. Therefore, adequate dietetic and pharmacologic treatments of the lipoprotein metabolic disorder as well as alcohol abstinence are highly impor- tant in preventing relapses of pancreatitis. The role of hypercalcemia as a cause of acute pancre- atitis, although classically accepted, should be nowa- days reevaluated. Although the association between hyperparathyroidism and pancreatitis has been repeat- edly reported, other potential causes of pancreatitis are also frequently present in these patients. The reported incidence of pancreatitis in patients with hyperparathy- roidism is very low. In addition, some series have shown that the risk of pancreatitis in these patients is similar to that observed in the general hospital population. In summary, hypercalcemia should be considered as the potential cause of acute pancreatitis only after exclu- sion of any other potential cause of the disease. Drugs A large variety of drugs have been related to acute pan- creatitis, most of which have been published only as case reports. Based mainly on the repeated report of a drug as associated with acute pancreatitis and the re- lapse of the disease with reintroduction of the drug, the strength of association between drugs and pancreatitis has been classified as definite, probable, or possible (Table 5.2). CHAPTER 5 41 Table 5.1 Causes of acute pancreatitis. Toxic and metabolic Alcohol Hyperlipidemia Hypercalcemia Drugs Scorpion venom Mechanical Gallstones, biliary sludge Ampullary obstruction Pancreatic obstruction Sphincter of Oddi dysfunction Pancreas divisum Trauma Congenital malformations Others Ischemia Iatrogenic injury Infection Hereditary Autoimmune Cystic fibrosis Tropical Although some drugs such as diuretics, sulfon- amides, and steroids are able to cause acute pancreatitis through a direct toxic effect, most cases of drug-related pancreatitis are probably due to individual hypersensi- tivity. In fact, potentially pancreatotoxic drugs are not independent risk factors for acute pancreatitis in large epidemiologic studies. The interval from the beginning of drug intake to the development of pancreatitis is highly variable, ranging from a few weeks in drug- induced immunologic reaction to many months when accumulation of toxic metabolites is required (e.g., valproic acid, pentamidine, didanosine). Obstruction to the flow of pancreatic juice The presence of pancreas divisum, defined as the ab- sence of fusion of the ventral and dorsal pancreatic ducts during fetal development, is an accepted risk fac- tor for acute pancreatitis. The mechanism by which pancreas divisum may cause pancreatitis is the obstruc- tion of flow of pancreatic juice through the minor papil- la. The relative risk of pancreatitis in subjects with this anatomic variant ranges from 2.7 to 10 times higher than in the general population. This means that 2–12 patients with pancreas divisum should be treated (e.g., by sphincterotomy of the minor papilla with or without stent insertion) to prevent one episode of acute pancre- atitis. It should be noted that, despite endoscopic treat- ment, 10–24% of patients with pancreas divisum relapse within the following 2 years. Acute pancreatitis secondary to sphincter of Oddi dysfunction usually presents as relapsing attacks in pa- tients with a dilated Wirsung duct and intrapapillary stenosis (type I dysfunction) or in patients with normal- appearing Wirsung duct but a basal sphincter of Oddi pressure higher than 40 mmHg (type II dysfunction). The pathogenesis of pancreatitis secondary to sphinc- ter of Oddi dysfunction is based on the obstruction of flow of pancreatic juice through the papilla. Because of this, endoscopic sphincterotomy is the treatment of choice in these patients and the best results have been obtained by cutting both the pancreatic and biliary sphincters. Any other condition causing obstruction of the papilla is potentially able to cause acute pancreatitis, including periampullary diverticula and periampullary tumors. Other potential etiologic factors The hereditary basis of pancreatitis has received great attention over the last few years. This is mainly due to the finding of frequent genetic mutations predisposing to pancreatitis in patients with no other potential etio- logic factor of the disease. In addition, some mutations may be necessary for the development of acute pancre- atitis in the presence of other etiologic factors. Cationic trypsinogen gene mutations are found in up to 50% of patients with a positive family history of pancreatic diseases compared with only 0–15% of those with- out family history. Some mutations of the cationic trypsinogen gene are associated with a high penetrance and seem to play a key role in the development of inher- ited pancreatitis. Conversely, mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene proba- PART I 42 Table 5.2 Drugs associated with acute pancreatitis. Definite association Valproic acid Azathioprine Didanosine Estrogen Furosemide (frusemide) 6-Mercaptopurine Pentamidine Sulfonamides Tetracycline Tamoxifen Probable association L-Asparaginase Steroids Metronidazole Aminosalicylates Thiazides Possible association Amphetamine (amfetamine) Cimetidine Cyproheptadine Cholestyramine (colestyramine) Diazoxide Histamine Indomethacin (indometacin) Isoniazid Propoxyphene Rifampicin Opiates bly act as disease modifiers. Nevertheless, the role of most described pancreatitis-associated gene mutations is still poorly understood and many other gene muta- tions are as yet unidentified. A wide variety of infectious agents have been associ- ated with acute pancreatitis. Although the scientific lit- erature in this field is mainly based on case reports, a definite association with acute pancreatitis is accepted for some microorganisms (Table 5.3). Because of doubtful therapeutic consequences during the acute at- tack, as well as to prevent relapses, the routine search for an infectious agent in patients with otherwise idio- pathic pancreatitis is not recommended. Pancreatic ischemia is an accepted cause of acute pancreatitis. Diagnosis of pancreatitis may be difficult in these patients, mainly in severe cases under intensive care such as after intraoperative hypotension or hemor- rhagic shock. Ischemia-related relapsing pancreatitis has been described in patients with systemic lupus ery- thematosus and polyarteritis nodosa. Finally, acute iatrogenic pancreatitis may develop after invasive maneuvers on the pancreas. The pro- totype of this is the pancreatitis occurring after endo- scopic retrograde cholangiopancreatography (ERCP). Acute pancreatitis develops in up to 5% of patients undergoing ERCP. Since abdominal discomfort or even pain in the absence of pancreatitis is not unusual after ERCP and since hyperamylasemia occurs in up to 70% of patients after ERCP, diagnosis of post-ERCP pancreatitis requires the presence of persistent severe abdominal pain and increased serum levels of pan- creatic enzymes greater than five times the upper limit of normal. Recommendations for etiologic diagnosis of acute pancreatitis in clinical practice Considering the high morbidity and the risk of mortali- ty secondary to acute pancreatitis, etiologic diagnosis of the disease is highly desirable in order to apply thera- peutic measures to prevent relapses. Up to 80% of acute pancreatitis episodes may be explained by gall- stones or alcohol consumption. Thus, etiologic diagno- sis may be easy in most cases by clinical history (history of biliary disease or alcohol consumption), standard hematologic and biochemical analysis (macrocytosis as a sign of chronic alcohol abuse; liver enzymes, mainly alanine aminotransferase (ALT) for biliary etiology, as- partate aminotransferase and g-glutamyltransferase for alcoholic pancreatitis), and abdominal ultrasound (presence of direct or indirect signs of gallstones). Bio- chemical analysis at admission should include serum triglyceride and calcium levels to support or exclude the potential role of serum lipids and hypercalcemia in the development of acute pancreatitis. Finally, history should include family history of pancreatitis (inherited disease?), a careful questionnaire about medications (drug-induced pancreatitis?), and associated auto- immune disorders (autoimmune pancreatitis?) (Fig. 5.1). Because of the important role of gallstones in the etiopathogenesis of acute pancreatitis, any finding sup- porting the presence of gallstone disease is sufficient to classify an attack of acute pancreatitis as biliary- related. All patients with acute pancreatitis should undergo abdominal ultrasound, searching for chole- cystolithiasis, common bile duct stones, or signs of biliary obstruction (biliary tract dilatation). A close relationship has been described between circulating levels of ALT at admission and acute biliary pancreati- tis. In this sense, a serum ALT level greater than two or three times the upper limit of normal has a positive predictive value of 95% for the diagnosis of gallstone CHAPTER 5 43 Table 5.3 Infectious agents associated with acute pancreatitis. Viruses Mumps Coxsackievirus Hepatitis B Cytomegalovirus Varicella-zoster Herpes simplex Human immunodeficiency virus Bacteria Mycoplasma Legionella Leptospira Salmonella Fungi and parasites Aspergillus Toxoplasma Cryptosporidium Ascaris [...]... 7.15–7 .24 111–119 < 55 7.15 110 61–70 7 .25 –7. 32 120 – 129 3–3.4 0.6–1.4 46–49.9 15–19.9 +2 30–45.9 3–14.9 < 2. 5 2. 5 2. 9 < 0.6 < 20 70 7.33–7.49 130–149 110– 129 110–139 500 70–109 70–109 12 24 5.6–5.9 130–159 140–179 35–49 36–38.4 25 –34 160 180 50 7 2 3.4 155–159 6–6.9 3.5 60 40 +1 0 1.5–1.9 50–59.9 20 –39.9 +3 +4 34–35.9 32 33.9 30–31.9 29 .9 40–54 10–11 50–69 55–69 6–9 49 39 5 55–60 7.15–7 .24 111–119 < 55 7.15 110 61–70 7 .25 –7. 32 120 – 129 ... J Clin Gastroenterol 20 02; 34:167–176 Viedma JA, Pérez-Mateo M, Domínguez-Muñoz JE, Carballo F Role of interleukin-6 in acute pancreatitis: comparison with C-reactive protein and phospholipase A Gut 19 92; 33: 126 4– 126 7 Werner J, Hartwig W, Uhl W, Müller C, Büchler M Useful markers for predicting severity and monitoring progression of acute pancreatitis Pancreatology 20 03;3:115– 127 55 7 Role of imaging... multicenter study Dig Dis Sci 1993;38:507–5 12 Johnson CD, Toh SKC, Campbell MJ Combination of APACHE-II score and an obesity score (APACHE-O) for the prediction of severe acute pancreatitis Pancreatology 20 04;4:1–6 Kylänpää-Bäck ML, Takala A, Kemppainen EA et al Procalcitonin strip test in the early detection of severe acute pancreatitis Br J Surg 20 01;88 :22 2 22 7 Lankisch PG, Blum T, Maisonneuve P, Lowenfels... pancreatitis Is this possible? J Pancreatol 20 02; 3:116– 125 54 Beechy-Newman N, Rae D, Sumar N, Hermon-Taylor J Stratification of severity in acute pancreatitis by assay of trypsinogen and 1-prophospholipase A2 activation peptides Digestion 1995;56 :27 1 27 8 Büchler M, Malfertheiner P, Schoetensack C et al Sensitivity of antiproteases, complement factors and C-reactive protein in detecting pancreatic necrosis:... Int J Pancreatol 1995;18:101–106 Fortson MR, Freedman SN, Webster PD III Clinical assessment of hyperlipidaemic pancreatitis Am J Gastroenterol 1995;90 :21 34 21 39 45 PART I Hanck C, Singer MV Does acute alcoholic pancreatitis exist without pre-existing chronic pancreatitis? Scand J Gastroenterol 1997; 32: 625 – 626 Kaw M, Brodmerkel GJ Jr ERCP, biliary crystal analysis and sphincter of Oddi manometry in... differentiation between mild and severe disease with high accuracy on admission, within the first 24 hours from onset of symptoms Plasma PMN elastase reaches maximum levels between 24 and 48 hours after Pancreatic damage Activation of inflammatory cells Activation of proteolytic cascades O2FR, IL-8 Endothelial lesion O2FR, PMN elastase, IL-1, IL-6, IL-18, PAF, TNF Multiorgan failure 52 Ischemia Figure 6.1... (PMN) elastase, tumor necrosis factor (TNF), IL-6 and IL-8, and C-reactive protein (CRP) should be underlined Although markers of inflammation are obviously not specific for acute pancreatitis, they can be used not only for early prognostic evaluation of the disease but also for monitoring its clinical course The correlation between plasma levels of PMN elastase and severity of acute pancreatitis is so close... counseling is mandatory before and after performing any genetic test Laboratory tests for autoimmunity (serum autoantibodies, total IgG, and IgG subtypes, mainly IgG4) should also be performed even in the absence of any other autoimmune disorder if no other potential cause of acute relapsing pancreatitis is detected (Fig 5 .2) Recommended reading Carballo F, Domínguez-Muñoz JE, Martínez-Pancorbo C, de . 35–49 25 –34 12 24 10–11 6–9 t 5 Oxygenation† A-aDO 2 (mmHg) u 500 350–499 20 0–349 < 20 0 Pa O 2 (mmHg) > 70 61–70 55–60 <55 Arterial pH u 7.7 7.6–7.69 7.5–7.59 7.33–7.49 7 .25 –7. 32 7.15–7 .24 . secreted in pancreatic juice in two isoforms (trypsinogen-1 and trypsinogen -2 ) . In acute pancreati- tis, trypsinogen -2 levels rise in both serum and urine over 10-fold. In two trials of approximately. 1996;110:1905–1908. Hedstrom J, Kemppainen E, Andersen J et al. A comparison of serum trypsinogen -2 and trypsin -2 a 1 -antitrypsin complex with lipase and amylase in the diagnosis and assessment of serverity