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Evaluación de-laboratorio-en-pancreatitis-2002

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Evaluación de-laboratorio-en-pancreatitis-2002

  1. 1. A Critical Evaluation of Laboratory Tests in Acute Pancreatitis Dhiraj Yadav, M.D., N. Agarwal, M.D., F.R.C.S., and C. S. Pitchumoni, M.D., M.A.C.G. Division of Gastroenterology and Department of Surgery, Our Lady of Mercy University Medical Center, New York Medical College, Bronx, New York ABSTRACT An ideal laboratory test in the evaluation of a patient with acute pancreatitis (AP) should, in addition to accurately establishing the diagnosis of AP, provide early assessment of its severity and identify the etiology. None of the tests available today meet all these criteria, and presently there is no biochemical test that can be considered the “gold stan- dard” for the diagnosis and assessment of severity of AP. In the diagnosis of AP, serum amylase and lipase remain important tests. Advantages of amylase estimation are its technical simplicity, easy availability, and high sensitivity. However, its greatest disadvantage is its low specificity. A normal amylase would usually exclude the diagnosis of AP, with the exception of AP secondary to hyperlipidemia, acute exacerbation of chronic pancreatitis, and when the estima- tion of amylase is delayed in the course of the disease. The major advantage of lipase is an increased sensitivity in acute alcoholic pancreatitis and in patients who initially present to the emergency room days after the onset of the disease, as lipase remains elevated longer than amylase. Although once considered to be specific for AP, nonspecific elevations of lipase have been reported in almost as many disorders as amylase, thus decreasing its specificity. Simultaneous esti- mation of amylase and lipase does not improve the accu- racy. Other enzymes for the diagnosis of AP—pancreatic isoamylase, immunoreactive trypsin, and elastase—are more cumbersome and expensive and have no clear role in the diagnosis of AP. No enzyme assay has a predictive role in determining the severity or etiology of AP. Once the diagnosis of AP is established, daily measurements of en- zymes have no value in assessing the clinical progress of the patient or ultimate prognosis and should be discouraged. A host of new serological and urinary markers have been investigated in the last few years. Their main use is in predicting the severity of AP. At present, serum C-reactive protein at 48 h is the best available laboratory marker of severity. Urinary trypsinogen activation peptides within 12–24 h of onset of AP are able to predict the severity but are not widely available. Serum interleukins 6 and 8 seem promising but remain experimental. (Am J Gastroenterol 2002;97:1309–1318. © 2002 by Am. Coll. of Gastroenter- ology) INTRODUCTION The diagnostic tests in the evaluation of a patient with suspected acute pancreatitis (AP) must answer three ques- tions sufficiently early in the course of the disease: first and foremost, the tests should establish the diagnosis accurately, excluding other conditions that mimic AP with or without hyperamylasemia. Second, at the earliest they should pro- vide an assessment of severity of AP to provide appropriate treatment in the required setting: intensive care unit versus a regular floor or by an internist alone versus a team of medical specialists that includes a surgeon, radiologist, and gastroenterologist trained in therapeutic endoscopy. Third, tests should also help in establishing the etiology for AP, so as to offer a definitive treatment such as cholecystectomy and/or to prevent recurrences of AP, as in the case of a patient with hyperlipidemic AP. The tests should be easily available, cost-effective, and easily repeatable. Obviously, every patient should not undergo all tests. This article, an extension of a number of recent reviews on the topic, including ours published in 1990 in this journal (1), critically evaluates the standard serum and urine tests and discusses the advances in laboratory technology that may have new diagnostic possibilities. In addition to our previous article on this topic (1), we have included relevant articles after 1990, using a broad-based MEDLINE search using the terms acute pancreatitis, diagnosis, laboratory tests, and severity. Relevant articles as well as their refer- ences were reviewed. SERUM TESTS FOR DIAGNOSIS OF AP A host of serum enzymes such as amylase, lipase, trypsino- gen, elastase, phospholipase A2, ribonuclease, etc are avail- able to diagnose AP and/or to assess the severity, but ele- vated amylase levels continue to be the “gold standard” among the serum markers. Serum Amylase In AP, serum amylase rises as a result of both increased release and, to some extent, reduced catabolism. The most familiar units of expression are the Somogyi unit (SU) and the international unit (IU). One SU per 100 ml is equivalent to 1.85 IU/L. The normal values are 60–160 SU/100 ml or THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 97, No. 6, 2002 © 2002 by Am. Coll. of Gastroenterology ISSN 0002-9270/02/$22.00 Published by Elsevier Science Inc. PII S0002-9270(02)04122-9
  2. 2. 110–300 IU/L in serum and 35–260 SU/h or 65–480 IU/L in urine (2). SENSITIVITY. The sensitivity of any test is dependent on the criteria used for diagnosis. If the test itself is taken as a criterion for diagnosis, as is often the case for serum amy- lase in AP, its sensitivity will be artificially raised to 100% (3). In one cohort (4), a 99.6% sensitivity for serum amylase reflected such subjective inclusion criteria. However, the sensitivity decreases to 81–95% when CT scan or ultra- sound is used to ascertain the clinical diagnosis of AP (5, 6). Normoamylasemia is reported in 19–32% of patients with AP (6, 7). Diagnosis of AP is questioned if the amylase level is normal. However, there are three major factors that lower the sensitivity: 1. Time interval since onset of attack. A major confounding factor is the variable time elapsed between the onset of the symptoms and the first blood analysis in a given patient. Within 24 h of the onset of symptoms, all en- zymes are elevated; thus, serum amylase is as sensitive as serum lipase, pancreatic isoamylase (P-isoamylase), im- munoreactive trypsin, or elastase (8). Amylase is the first one to return toward normal values, and as such, after the first hospital day it is the least sensitive of the enzymatic tests for pancreatitis. Normalization can sometimes occur very rapidly, indicating early resolution of the disease, increased urinary clearance, or, less frequently, extensive destruction of the pancreas with cessation of pancreatic amylase production (6). 2. Alcoholic pancreatitis. Spechler et al. (7) noted that patients with acute alcoholic pancreatitis frequently (32%) have normal serum amylase levels. Furthermore, in patients with alcoholic AP, normoamylasemia was significantly associated with number of previous attacks (0.7 vs 0.4, p Ͻ 0.01), indicating a parenchyma that is no longer able to produce sufficient amounts of enzymes (6). 3. Hypertriglyceridemia. Serum or urinary amylase levels may be normal in as many as 50% of patients with abdominal pain and hypertriglyceridemia, in whom a clinical diagnosis of AP is considered and when CT shows pancreatic inflammation (9). The hyperlipidemia interferes with the amylase assay, leading to a spuriously normal result. A circulatory inhibitor of serum amylase exists, as suggested by demonstration of elevated amy- lase by dilution of the serum (10), but is probably not triglyceride itself (11). In all situations where AP is suspected with a normal serum amylase, triglyceride estimations must be done, and if lactescent plasma is present, serial dilution techniques should be employed to circumvent false negative amylase results. SPECIFICITY. The greatest limitation of serum amylase is its lack of specificity. Besides AP, conditions that increase serum amylase levels include many diseases and derange- ments of the biliary tract, liver, intestines, genitourinary tract, lungs, breast, prostate, central nervous system, and, of course, salivary glands (12). Abnormal serum levels also occur in the presence of metabolic disturbances such as renal failure, liver dysfunction, diabetic ketoacidosis, hypo- perfusion, eating disorders like anorexia nervosa and bu- limia (13), and abdominal and nonabdominal trauma includ- ing head injury, as well as with the use of various drugs (2, 14). Interestingly, hyperamylasemia, seen commonly in HIV-infected persons and in up to 40% of intoxicated al- coholics, often does not signify AP, as predominantly S- type amylase levels alone go up (15, 16). An important observation is that, after ERCP, hyperamylasemia is noted in 25–43% of patients but only 1–4% have evidence of pancreatitis (17). Furthermore, persistent hyperamylasemia may be a normal variant (18) and has been recently de- scribed as a benign abnormality in many members of certain families (19) (Table 1). Another critical limiting factor that significantly influ- ences the specificity is the issue of what signifies an abnor- mal value (3). More than 200 techniques of amylase deter- mination are described in the literature, creating a host of “normal” values that differ both quantitatively and in meth- ods of expression (2, 20). Further, different studies have arbitrarily used various cutoff values ranging from just the upper limit of normal (300 IU/L) (3) to more than three times the upper limit of normal (Ͼ1000 IU/L) (21). No international reference method or cutoff value has yet been adopted toward establishing a standardized tool. With a cutoff value of 300 IU/L (upper limit of normal), total amylase has a sensitivity of 91–100% but a specificity of 71–98%. Increasing the cutoff value to 1000 IU/L increases the specificity to around 100% but decreases sensitivity to as low as 61%. Ideally, sensitivity should be increased at the Table 1. Conditions With Increased Amylase Abdominal disorders Pancreatic disorders: acute pancreatitis, chronic pancreatitis, pseudocysts, pancreatic trauma, pancreatic cancer Nonpancreatic intra-abdominal conditions: perforated bowel, mesenteric infarction, intestinal obstruction, appendicitis, peritonits, abdominal aortic aneurysm, ruptured ectopic pregnancy, fallopian and ovarian cysts, salpingitis, hepatitis Extra-abdominal conditions Salivary diseases, renal failure, ketoacidosis, pneumonia, cerebral trauma, burns, anorexia nervosa, bulimia, nonabdominal surgery Macroamylasemia Idiopathic hyperamylasemia Familial and nonfamilial Drug induced Definite association: azathioprine, L-asparginase, sulfonamides, tetracycline, didanosine, methyldopa, estrogens, furosemide, pentamidine, 5-aminosalicylic acid compounds, valproic acid, salicylate, thiazide, calcium, vinca alkaloids Probable association: glucocorticoids, nitrofurantoin, phenformin, rifampin, FK-506 (tacrolimus), metronidazole, 6-mercaptopurine, procainamide, diphenoxylate, chlorthalidone, cimetidine, cytosine arabinoside, cisplatin, cyclosporin A 1310 Yadav et al. AJG – Vol. 97, No. 6, 2002
  3. 3. expense of specificity when the penalty associated with missing the disease is high. On the other hand, specificity should be increased relative to sensitivity when the costs or risks associated with further diagnostic techniques are sub- stantial. Because AP can be serious, it is wiser to increase the sensitivity at the expense of specificity. SEVERITY OF AP. Virtually all investigators agree that the magnitude of increase in amylase activity does not correlate with the severity of the disease. It is even possible for patients with very severe necrotizing AP to have normal or low values of amylase, indicating an inverse relationship between the amylase level and the severity of the disease (22, 23). Clinically, AP does not seem to behave differently when serum amylase is normal or elevated (6, 24). Once the diagnosis of AP is established, daily measurements of serum amylase have little value in assessing the clinical progress of the patient or ultimate prognosis (25). However, persistent hyperamylasemia that does not return to normal within 5–10 days has been shown to correlate with complications such as pseudocysts, necrosis, or abscess. ETIOLOGY OF AP. In general, patients with biliary pan- creatitis have markedly higher initial serum amylase levels than those with alcoholic pancreatitis or pancreatitis from other causes. Hiatt et al. (26) observed that only 11% of patients with biliary disease had initial serum amylase val- ues lower than 1000 IU/L, whereas only 6% with alcoholic pancreatitis had initial amylase values higher than 1000 IU/L. CLINICAL PRACTICE RECOMMENDATIONS. The ad- vantage of serum amylase estimation lies in its technical simplicity and ready availability in all hospitals. In contrast, its greatest disadvantage is its overall low specificity. Be- cause the presence of a raised serum amylase in the clinical setting of abdominal pain is not entirely specific, it is de- sirable to confirm it by imaging studies. A normal amylase level would nearly exclude the diagnosis, with the excep- tions of possible hyperlipidemic pancreatitis, acute exacer- bation of chronic pancreatitis, and delayed estimation in the course of the disease. Indeed, AP should not be dismissed in the presence of an amylase level that is either normal or only mildly elevated on initial evaluation if the clinical suspicion for AP is high and it is prudent to seek additional tests. Serum amylase has no value in assessment of severity or etiology of AP. Lipase Lipase (triacylglycerol acylhydrolase) is mainly synthesized and stored as granules in the pancreatic acinar cells. More than 99% is subsequently excreted in the ductal systems, and less than 1% diffuses via the lymphatics and capillaries into the general circulation (27). The concentration gradient between pancreatic tissue and serum is over 20,000-fold. Other sources of lipase are the tongue, esophagus, stomach, duodenum, leukocytes, adipose tissue, lung, and breast milk. However, the lipase concentration in the pancreas is 100- fold greater than in the liver, duodenum, and small bowels (28). In AP, increased permeability in the basal pole of the acinar cells accounts for the pronounced rise of the enzyme in the serum. Usually, serum lipase increases within 4–8 h after onset of symptoms, peaks at 24 h, and returns to normal after 8–14 days (29). Lipase assay is fast, reliable, practical, and almost as sensitive as an amylase assay. The cost of the lipase assay compares favorably with amylase assays, and the technique can be available 24 h a day, 7 days a week in most hospitals. SENSITIVITY. The sensitivity of lipase ranges from 85% to 100% (3, 21), with some reporting it to be less sensitive than serum amylase (3) and others believing it to be more sensitive than amylase (21, 30). The major advantage of lipase is an increased sensitivity in acute alcoholic pancre- atitis and with late clinical presentation, as lipase remains elevated longer than does amylase. Clavien et al. (6) found that in patients with AP who had normal amylase, more than two thirds had elevated lipase levels. Gumaste et al. have shown in their study on patients with AP and nonpancreatic abdominal pain (31) that the sensitivity of lipase levels of greater than three times normal is much higher than amylase levels (100% sensitivity and 99% specificity, vs 72% sen- sitivity and 99% specificity for amylase levels). In a recent study of ERCP-induced AP (32), mean lipase values were four times higher than amylase levels 2 h after the procedure in those who developed AP. SPECIFICITY. Lipase elevation is not specific to AP, al- though it may be slightly better than amylase. Apple and associates (30) have shown that lipase activity is four times greater than amylase activity in the pancreas. Second, pan- creatic tissue in chronic pancreatitis demonstrates a substan- tial decline in both amylase and lipase activity, with amylase activity showing a greater decrease compared to lipase (91% vs 26%). In conditions of extrapancreatic injury, lipase is also elevated. Mumps, types I and IV hyperlipoproteine- mias, peptic ulcer, acute cholecystitis, extrahepatic biliary obstruction, liver diseases, small bowel obstruction, intesti- nal infarction, perforated bowel, acute renal failure, fracture of bone, crush injury, fat embolism, and the postcholecys- tectomy syndrome are some examples (7, 33). In our study of patients with diabetic ketoacidosis (34) we found non- specific elevation of lipase to occur more frequently than amylase elevation. Recently, inflammatory bowel disease and familial pancreatic hyperenzymemia have been in- cluded among causes of lipase elevation (19, 35). The reference point determined in different laboratories may differ even for identical methods (27, 36). Further, different authors have arbitrarily used different cutoff val- ues. Steinberg et al. (3) have shown that the upper limit of normal itself provided the best cutoff value. Keim and associates (5) suggest that 2-fold elevated lipase values should be used as the cutoff, whereas Gumaste et al. (31) 1311AJG – June, 2002 Evaluation of Laboratory Tests in Acute Pancreatitis
  4. 4. advocate a cutoff level of three times normal. They observed that when lipase elevation is not due to AP, the elevation is usually less than three times normal. However, Frank and Gottlieb (29) have reported patients with lipase greater than three times normal secondary to renal insufficiency, malig- nant tumors, cholecystitis, esophagitis, and hypertriglyceri- demia. Other major disadvantages of lipase assay are a) presence of as many as four fractions of lipase in serum of patients with pancreatitis, b) the macroforms or macroli- pasemia contribute to hyperlipasemia, and c) technical dif- ficulties are more with lipase assays than amylase assays (27, 36, 37). CLINICAL PRACTICE RECOMMENDATIONS. The major advantage of lipase is an increased sensitivity in acute alcoholic pancreatitis and late clinical presentation, as lipase remains elevated longer than amylase. Its specificity may be slightly better than amylase; however, it is increasingly being recognized that nonspecific elevations of lipase can be seen in as many disorders as amylase. Serum lipase also has no value in assessment of severity or etiology of AP. Amylase, Lipase, or Both Controversy exists whether amylase and lipase should be used alone or in combination to avoid overlooking patients with AP. Opinions vary on the preferential test (38). Al- though amylase continues to be the screening test for AP (3, 6, 39), a number of studies have challenged the primary diagnostic role of serum amylase, and a case has been made for the use of serum lipase instead (31, 40, 41). Within 24 h after onset of symptoms, both amylase and lipase values have high sensitivity and specificity, with lipase having a slightly higher diagnostic value. Amylase appears to be a better test in gallstone pancreatitis and lipase from alcoholic and other causes. The differences in perfor- mance of the two tests, though small, are definite (42). Simultaneous evaluation of amylase and lipase does not improve the accuracy (5, 43). Other Tests of Limited or No Value Normal circulating amylase consists of P-isoamylase (40% of total amylase) and a salivary-type isoamylase (60%) (18). In AP, P-isoamylase is expected to rise; hence the estima- tion of this fraction is theoretically attractive. Importantly, some nonpancreatic abdominal emergencies such as acute biliary tract disease, perforated duodenal ulcer, intestinal obstruction, infarction, and ruptured abdominal aortic aneu- rysm are also associated with an increase in P-isoamylase. Thus, a major group of differential diagnoses is not elimi- nated (44), and therefore, measurement of isoenzymes in the serum has been largely abandoned (25). Macroamylases are large molecules of amylase where abnormal proteins—IgA, IgG, or IgM—produce a large molecular weight complex that cannot be cleared through the kidneys (45). It occurs in 0.1% of the population (46) and in up to 2.7% of hospitalized patients (47). In a large majority of individuals macroamylasemia is not clinically significant. However, in an asymptomatic individual with elevated serum amylase, which causes concern, an estima- tion of urine amylase that shows low levels will settle the issue. Immunoreactive trypsinogen (IRT) has a sensitivity of 97–100%, a specificity of 83%, and a positive predictive value of 46–74% (3, 8). However, the levels are also high in malignant neoplasms of the pancreas, diabetes mellitus, chronic renal failure, hypercalcemia, hypertriglyceridemia, cirrhosis of the liver, chronic pancreatitis, and extrahepatic obstructive jaundice (48). Therefore, many believe that IRT helps to confirm the pancreatic origin of a raised serum amylase, but does not much improve the diagnostic accu- racy in patients with suspected AP with normal or only mildly elevated amylase. IRT is a more difficult test to perform and requires 24 h to complete. Elastase-1, a proteolytic enzyme liberated in the course of AP, has a specific elastolytic action that is responsible for digestion of blood vessel walls and vascular complications. By radiommunoassay, one can demonstrate elevated elas- tase levels in the serum in all cases of AP. The test, however, lacks specificity, as it is elevated in two thirds of pancreatic cancer patients and less frequently in chronic pancreatitis (17). Also, serum elastase levels did not correlate with disease severity or development of complications. It is also unable to discriminate between alcohol and gallstone pan- creatitis (8). Elastase confers no benefit as a diagnostic test nor does it provide any prognostic information. The only strength of IRT and elastase assays is that they remain elevated for 7–10 days after the onset of AP, and elastase is the more sensitive of the two. Their determination may be indicated in patients who present late and in whom the diagnosis of pancreatitis is in doubt. CLINICAL PRACTICE RECOMMENDATIONS. Pres- ently, there is no role of isoamylases, IRT, macroamylases, and elastase estimations in the routine management of pa- tients with AP. SERUM MARKERS OF SEVERITY OF AP Hematocrit Recently, hemoconcentration has been identified to be a strong risk factor and early marker for necrotizing pancre- atitis and organ failure (49, 50). An admission Hct of Ն47 and a failure of admission Hct to decrease at 24 h represent a strong risk factor for the development of pancreatic ne- crosis. Baillargeon et al. (49) compared 32 patients with necrotizing pancreatitis to an equal number of patients with mild pancreatitis. At 24 h, 81% (26/32) of patients met either of the criteria (admission HCT Ն 47 or failure of HCT to decrease), compared to 12.5% (4/32) of those with mild AP (p Ͻ 0.01). The sensitivity and specificity using these criteria on admission were 34% and 91% and, at 24 h, 81 and 88%, respectively. 1312 Yadav et al. AJG – Vol. 97, No. 6, 2002
  5. 5. C-Reactive Protein (CRP) Serum CRP is an acute phase reactant that is elevated in several inflammatory conditions and serves as a nonspecific marker for inflammation. CRP levels peak on the 3rd or 4th day, and values of Ͼ150 mg/L when done 48 h after the onset of symptoms are now accepted as a proven predictor of severity of AP (42). In a study by Wilson et al. (51), peak CRP levels of Ն210 mg/L were able to differentiate severe AP from the milder form with a sensitivity of 83–84% and a specificity of 74–85%. Another recent study (52) has shown CRP to be superior to interleukin 1B (IL-1B), IL-8, and tumor necrosis factor ␣ (TNF-␣) and equivalent to IL-6 in predicting severe pancreatitis on day 2. CRP has also been reported to have an overall accuracy of 93% in detect- ing pancreatic necrosis. Serum CRP therefore is considered to be the gold standard for predicting severity of AP (51– 55). CRP is widely available, easy to measure, and cheap to perform. The major drawback of CRP is that it takes 48–72 h to peak, a delay similar to other methods used for severity assessment in AP. Polymorphonuclear Elastase In severe AP, neutrophils accumulate in the pancreas, pro- ducing lysosomal proteases—mainly elastase—and a major factor for pancreatic necrosis. It also causes activation of complement, kinins, and fibrinolytic systems, leading to multiple organ system failure. Obviously, estimation of PMN elastase is not a diagnostic test for AP but may indicate severity. Uhl et al. (56) have shown that elastase levels differentiate edematous from necrotic pancreatitis. The PMN elastase level is comparable to CRP in predicting necrosis. Its advantage over CRP is that its peak levels are reached on day 1 of onset and the levels fall rapidly in patients with edematous pancreatitis, compared to CRP val- ues, which remain elevated. Pancreatitis-Associated Protein (PAP) PAP, an acute phase protein, is secreted from pancreatic acinar cells (57, 58), especially in AP. It induces extensive bacterial aggregation and thus may play a role in the pre- vention of bacterial infection in AP. PAP levels have been correlated with severity of pancreatitis in rats (59) and humans (60), suggesting a prognostic role. Phospholipase A2 and Ribonuclease Phospholipase A2 and ribonuclease are elevated in AP but not in healthy individuals. Phospholipase A2 is produced in the pancreas and also by neutrophil activation. Several stud- ies have also shown it to be a good early marker of severe pancreatitis (61–64). In a recent study by Mayer et al. (65), levels of secretory synovial-type phospholipase were signif- icantly higher in patients with infected necrosis than those with sterile necrosis, and levels of Ͼ300 ng/ml on 2 suc- cessive days within the first 4 days predicted infected ne- crosis with a high sensitivity and specificity. Warshaw and Lee (66) have reported a relationship between serum levels of pancreatic ribonuclease and the need for operative treat- ment of pancreatic necrosis or abscesses. They found that, among 24 patients with normal ribonuclease levels, only one required surgical treatment for abscesses. In contrast, 11 of 13 patients with elevated ribonuclease required surgical intervention. These relationships need further evaluation in a large group of patients. The assays are cumbersome and not currently available for clinical use. Interleukins The activation of inflammatory cells that release cytokines plays an important role in the pathogenesis of the disease. Various studies have demonstrated that IL-6 and IL-8 peak within the first 24 h after onset of symptoms and are sig- nificantly higher in patients with severe AP (67–72). A study of serum markers in ERCP-induced AP showed that the earliest peak was of serum IL-8, 12 h after the procedure, followed by IL-6’s peak at 24 h and CRP’s peak at 72 h. Chen and associates (52) have observed that, when com- pared to serum TNF-␣, IL-1B, IL-8, and CRP, IL-6 is the best early predictor (day 1 after admission) of severe AP. Using a cutoff value of Ͼ400 pg/ml, the sensitivity, speci- ficity, and accuracy were 89%, 87%, and 88%, respectively, on day 1. Furthermore, patients with fatal outcomes showed the most markedly elevated IL-6 concentrations (2–5 times the mean values in severe pancreatitis) on days 1 and 2, and they remained elevated on day 7. The disadvantage is that the routine determination of IL-6 is not yet widely available. A rapid dipstick method for estimation of IL-8 is also under investigation (72). In contrast, IL-10 reduces the inflammatory response in experimental pancreatitis. In humans, Pezzelli and associ- ates (68) have also observed higher levels of IL-10 in the sera of patients with mild disease. Tumor Necrosis Factor The prognostic significance of serum TNF in AP has not been established, as its release is variable and phasic. de- Beaux et al. (73) have shown that the concentration of soluble TNF receptors is able to differentiate mild, severe, and fatal attacks of AP. Banks et al. (74) observed no significant difference between mild and severe AP, whereas Chen and associates (52) found significantly elevated levels in severe AP on days 1–3 but not on days 4 and 7. The role of TNF assay as a prognostic marker remains unclear. Other Serum Markers Preliminary studies indicate serum procalcitonin to be a valuable marker for the prediction of infected pancreatic necrosis as well as septic multiorgan failure (75, 76). Sev- eral other markers have been evaluated recently to assess the severity of AP. These include plasma soluble intercellular adhesion molecule 1 (76, 77), serum levels of extracellular matrix (78), serum levels of the activation peptide of car- boxypeptidase B (79), serum amyloid A (80), and serum trypsinogen-2 and trypsinogen-2-␣-1-antitrypsin complex (81). The use of these tests is currently restricted to research 1313AJG – June, 2002 Evaluation of Laboratory Tests in Acute Pancreatitis
  6. 6. settings, and further studies defining their clinical impor- tance in assessment of severity of AP are awaited. Clinical Practice Recommendations for Serum Tests of Severity Although a host of newer serum markers hold promise for the future, they are still experimental, used in research settings, and not widely available. Serum CRP is the best available serum marker presently to assess the severity of AP. A cutoff level of Ͼ150 mg/L is now accepted as a proven predictor of severity. CRITERIA UTILIZING MULTIPLE LABORATORY TESTS Blood urea nitrogen with glucose levels have been shown to be helpful in identifying patients with severe AP (82). The most commonly used criteria for predicting severity are Ranson’s criteria (83), which include 11 signs with prog- nostic significance. The mortality is related to the number of these signs present: 0.9% with less than three positive prog- nostic signs, 16% with three or four, 40% with five or six, and 100% with more than six signs (84). A modification of Ranson’s signs as suggested by Osborne et al. (85) is used in the United Kingdom. They have excluded Hct, base deficit, and fluid sequestration, but included serum albumin of Ͻ3.2 g/dl as an important criterion of severity. Acute Physiology and Chronic Health Evaluation (APACHE-II) uses the worst values of 12 physiological measurements, age, and previous health status to provide a general measure of severity of disease (86). The physiolog- ical variables considered are temperature, mean arterial pressure, heart rate, respiratory rate, arterial oxygenation, arterial pH, serum sodium, serum potassium, serum creati- nine, Hct, white blood cell count, and Glasgow Coma Scale. An APACHE-II score of Ͼ8 indicates severe AP. The advantages of APACHE-II over other prognostic criteria are objective determination of AP within hours of admission and the ability to be recalculated daily so as to follow the course of the disease and response to therapy. LABORATORY TESTS TO PREDICT THE ETIOLOGY OF AP The height of amylase or lipase does not predict the etiology of AP. A reported benefit of estimating serum lipase is that it might suggest the etiology of AP. Gumaste et al. (87) found that a lipase/amylase ratio of Ͼ2 was suggestive of acute alcoholic pancreatitis. Several other studies have tried to determine the utility value of the lipase/amylase ratio (88–91). Although all studies did not agree that a lipase/ amylase ratio is a precise indicator, most reveal a definite trend—values of Ͼ3 are highly indicative of acute alcoholic pancreatitis, whereas low values (Ͻ1–2) are more sugges- tive of gallstone pancreatitis (90). Controversy still exists with regard to the utility of the ratio in clinical practice. A recent practice guideline article (25) did not recommend it. Table 2 summarizes the laboratory tests in AP. Several studies have looked at the utility of liver function tests in predicting gallstone pancreatitis (92–94). According to a recent meta-analysis (95), an ALT level of Ն150 U/L (approximately a 3-fold elevation) has a positive predictive value of 95% in diagnosing acute gallstone pancreatitis. However, the sensitivity is only 50%. Bilirubin and ALP were not found to be as useful as ALT (95). URINE TESTS Diagnosis Although routine use of urinary amylase is not done widely to evaluate a patient with AP, recently several studies have reported the use of urinary dipstick tests for screening cases of AP in the emergency room (96, 97). A dipstick test for detecting pancreatic amylase in urine by an immunochro- matography principle using the monoclonal antibodies spe- cific for pancreatic amylase in initial studies has shown promising results (97). The test has a high specificity of 97% and is likely to become useful in the emergency room setting. Other tests have reported the clinical utility of the urine trypsinogen-2 dipstick test in AP for screening pa- tients with suspected AP as well as predicting the severity (98, 99). In a study of 525 consecutive patients presenting to the emergency room with abdominal pain, the sensitivity and specificity of diagnosing AP were 96% and 92%, re- spectively. All nine patients with severe AP were detected by the dipstick (98). Severity Trypsinogen activation peptides (TAPs) are the highly con- served tetra-1-aspartyl-1-lysyl amino terminal peptides re- Table 2. Laboratory Tests in AP Tests for diagnosis Serum tests 1. Amylase 2. Isoamylases 3. Macroamylases 4. Lipase 5. Immunoreactive trypsin 6. Elastase Urine tests 1. Amylase 2. Lipase Fluid amylase Tests for severity Serum tests 1. CRP 2. Interleukins (IL-6, IL-8, etc) 3. Polymorphonuclear elastase 4. PAP 5. Phospholipase 6. Procalcitonin 7. TNF-␣ 8. Ribonuclease 9. Methalbumin Urine tests TAPs 1314 Yadav et al. AJG – Vol. 97, No. 6, 2002
  7. 7. leased during the activation of trypsinogen to trypsin. Though normally produced in the intestinal lumen after activation of trypsinogen by enterokinase, they are not ab- sorbed, because of degradation by enteric oligopeptidases (100–103). In AP, premature intrapancreatic activation of trypsinogen leads to the release of TAPs into blood, lym- phatics, and peripancreatic tissue, leading to increased con- centrations in body fluids. TAPs are liberated within the first few hours of the onset of AP, and they peak within 12–24 h of admission. Experimental studies done in animals and humans have found estimation of TAPs to be helpful as a prognostic marker in differentiating severe from mild AP. Gudgeon et al. in their study (103) found urinary TAP estimation to be much better than serum CRP levels. When a urinary con- centration of Ͼ2 nmol/L was used as a cutoff on admission, the sensitivity and specificity for predicting severe AP were 80% and 90%. When the highest concentration of TAPs in the first 24 h was used, the sensitivity and specificity of urinary TAP levels of Ͼ10 ng/ml were 100% and 85% in predicting severe AP (104). Neoptolemus and associates (105) in a prospective study compared levels of urinary TAPs with serum CRP and the three currently used scoring systems in 172 patients with AP (35 with severe disease) and 74 controls. Urinary TAP concentrations differed significantly between mild and se- vere AP at 24 h and 48 h after onset of symptoms and also at 24 h and 48 h after admission. CRP concentrations dif- fered significantly at 48 h but not at 24 h. TAPs at 24 h (Ͼ34 mmol/L) were similar to an APACHE-II score of Ͼ8 (0–12 h after admission) with respect to sensitivity (58% vs 58%), specificity (73% vs 76%), positive predictive value (39% vs 40%), negative predictive value (86% vs 87%), and accu- racy (70% vs 72%) (Table 3). CLINICAL PRACTICE RECOMMENDATIONS. The as- say of TAPs for determining severity of AP is appealing as a single marker that is able to provide accurate severity prediction within 24 h after onset of symptoms. These encouraging results should be considered preliminary, and further studies are needed to establish its role in the evalu- ation of AP. Presently, TAP assays are not widely available. ASCITIC FLUID ANALYSIS Early appearance of ascites is seen in over 60% of cases of severe AP (106). This peritoneal exudate is rich in activated lipolytic and proteolytic enzymes, vasoactive substances, and several other proinflammatory mediators. Ascites may play a role in the transfer of toxic mediators into the sys- temic circulation or may be a reflection of the locoregional necrotizing process (106). A peritoneal tap can provide corroborative evidence of AP by the presence of a high amylase concentration, especially if sterile fluid is aspirated (106). The biochemical composition of peritoneal fluid dur- ing AP, however, reveals no major differences between the principal etiological categories of AP (107, 108). McMahon et al. (109) have shown that volume and color of peritoneal fluid are indicators of the severity of an attack of AP. Severe AP is indicated in the presence of one or more of the following: greater than 20 ml of free peritoneal fluid, dark-colored free intraperitoneal fluid, and lavage fluid darker than a pale straw color obtained after peritoneal lavage with a liter of normal saline. However, peritoneal lavage is an invasive procedure that is not applicable for patients with mild disease and contraindicated in patients with previous scars, obesity, coagulopathy, or difficulty in catheterization. It is associated with visceral puncture in 0.8% of patients. It is also a poor system for accurate grading of patients with biliary pancreatitis (108). CLINICAL PRACTICE RECOMMENDATIONS. Diag- nostic peritoneal lavage is an invasive test and a poor system for grading the severity of AP. It has never been accepted widely into clinical practice. RESULTS AND DISCUSSION It is clear that there is no biochemical test that can be considered to be a gold standard for the diagnosis or assess- ment of severity of AP. Amylase and lipase remain impor- tant tests in the diagnosis of AP. Lipase, which was initially thought to be more specific than amylase, has recently been shown to be almost as nonspecific as amylase. The use of other tests like P-isoamylase, IRT, elastase, urinary amylase Table 3. Comparison of Laboratory Tests for AP Amylase Lipase Serum CRP Urinary TAPs Interleukins (IL-6, IL-8) Sensitivity 67–100%* 82–100% Test for severity Test for severity Test for severity Specificity 85–98% 82–100%† Test for severity Test for severity Test for severity Prediction of severity None None Yes (Ͼ150 mg/L at 48 h) Yes (peak within 12–24 h) Yes (peak within 12–24 h) Comments Cheap, widely available Cheap, widely available Cheap, widely available, best available lab test for severity Not widely available, expensive Experimental * Poor sensitivity in hyperlipidemic AP, acute or chronic AP due to alcohol, and delayed estimation. † Better than amylase. Lipase is increasingly being recognized as nonspecific. 1315AJG – June, 2002 Evaluation of Laboratory Tests in Acute Pancreatitis
  8. 8. and lipase, and fluid amylase has no clear role in the eval- uation of patients with AP. Urinary TAPs within 12–24 h and serum CRP at 48 h are now considered by many to be good markers for predicting severity of AP. A host of new serological markers have been investigated in the last few years to predict the severity of AP early. Some of them show promise but have yet to prove their superiority. Reprint requests and correspondence: C. S. Pitchumoni, M.D., M.A.C.G., M.P.H., Professor of Medicine and Preventive & Com- munity Medicine, New York Medical College, Director, Depart- ment of Medicine & Chief of GI, Our Lady of Mercy Medical Center, 600 East 233rd Street, Bronx, NY 10466. Received Feb. 6, 2001; accepted Jan. 15, 2002. REFERENCES 1. Agarwal N, Pitchumoni CS, Sivaprasad AV. Evaluating tests for acute pancreatitis. Am J Gastroenterol 1990;85:356–66. 2. Salt WB, Schenker S. Amylase—its clinical significance: A review of the literature. Medicine 1976;55:269–89. 3. 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