Pancreas divisum

Serum amylase and lipase levels are markers of pancreatic inflammation and are standard tests to diagnose acute pancreatitis. Lipase level is a more specific and sensitive index of pancreatic disease than amylase level, but an elevation of lipase levels three or less times the normal range may be nonspecific and rarely may predict significant pancreatic pathology. (1) Lipase activity may be measured using several methods, but considerable interassay discrepancies may be found. (2)

Lipase organ specificity for the pancreas is reduced in patients with renal insufficiency, (3-7) diseases of the liver, (8) alcohol abuse, (9,10) and in various intraabdominal (11-15) or extra-abdominal nonpancreatic diseases. (16-26)

Thus, in patients with renal failure and no abdominal pain, hyperlipasemia has been found in as much as 80%. (3) Elevations are not evident until creatinine clearance falls to < 50 mL/min. (4,5) The extent of increase is thought to be related to renal function (3) as well as to the modalities of dialysis that the patients received. (6) Furthermore, rises in serum lipase levels with hemodialysis have been observed, presumably because of the lipolytic effect of the heparin used during this procedure. (7) Accordingly, serum samples for lipase determination should be obtained before dialysis in these patients.

Among liver diseases, hyperlipasemia has been reported as a manifestation of chronic hepatitis C virus infection. A significant association between alanine transferase and lipase was observed. Interestingly, the normalization of high lipase levels has been reported only among responders to antiviral therapy. (8)

In asymptomatic alcoholics without acute pancreatitis, hyperlipasemia may be a common finding. Elevations of serum lipase levels have been found in 11 to 33% of these patients. (9,10) Most of them have levels that are one to two times the normal level, and no patient usually exceeds three times the normal level. (9) This background information is important in the interpretation of serum lipase levels in alcoholic patients with abdominal pain, because using an elevated serum lipase level to diagnose acute pancreatitis in an alcoholic patient with abdominal pain may not be appropriate.

GI disease may increase lipase values by two to three times the normal level. Thus, elevated serum lipase and amylase levels are observed in 14% of inflammatory bowel disease patients without clinical symptoms of a pancreatitis. Patients with Crohn disease have a slightly greater prevalence of hyperlipasemia than those of ulcerative colitis, although enzyme level increases are associated with more extensive and active inflammatory bowel disease. (11-13) Interestingly, a significant increase (greater than twice the normal standard) has been shown more often in lipase levels than in amylase levels, but a specific pancreatitis is not considered in such cases. (11) Although hyperlipasemia has been reported as an adverse event of therapy with some drugs (eg, azathioprine and salazosulfapyridine) that are commonly used to treat these patients, (14,15) no influence of the use of medication on enzyme levels has been shown. (12)

Elevations in serum lipase levels also may result from macrolipasemia, which is a complex of lipase enzyme-linked Igs, in which hyperlipasemia results from the combination of lipase with IgG, (16,17) IgA1-[kappa], (18) or [[alpha].sub.2]-macroglobulin, (19,20) rather than from pancreatitis. In rare instances, macrolipasemia also may be associated to macroamylasemia (18,21) or even may be accompanied by Crohn disease, (17) thus making a correct diagnosis difficult. In patients with anorexia nervosa or bulimia, increases in lipase levels have been described, but they have been unrelated to pancreatic disease. (22) Hyperlipasemia has also been reported in 25% of patients with diabetic ketoacidosis with unremarkable findings on CT scans of the pancreas and no objective evidence of abdominal pain. (23,24) In contrast to increases in amylase levels, the elevation of lipase levels has been found to be correlated with serum osmolality but not with pH in these patients. (24) In approximately 7% of patients with altered states of consciousness due to head injury or stroke, hyperlipasemia of nonpancreatic origin has been found. (25,26) As a result, a diagnosis of acute pancreatitis in all the above-mentioned clinical conditions based solely on elevated amylase or lipase levels, even to more than three times the normal level, is not justifiable. This knowledge may save these patients from invasive and costly examinations.

Elevated lipase levels from pancreatic origin other than pancreatitis can be seen in patients with blunt pancreatic trauma, (27,28) malignancy, (29,30) and, more rarely, sarcoidosis. (31) As a result, these differential diagnoses need to be considered in patients presenting with hyperlipasemia.

In critically ill patients who are admitted to the ICU with diagnoses other than pancreatitis, increased lipase levels have been observed. Thus, in patients who have undergone cardiac surgery, the incidences of symptomatic hyperlipasemia and documented pancreatitis after surgery have been found to be 1.3% and 0.1%, respectively. (32,33) However, there is little information about the incidence of these abnormalities among general ICU patients.

In this issue of CHEST (see page 246), Manjuck and colleagues have studied the incidence of hyperlipasemia of nonpancreatic origin among 245 critically ill patients on ICU admission. Because a major concern remains among critical care physicians when unsuspected hyperlipasemia is found in ICU patients, this is an interesting work that attempts to clarify the epidemiology of this subject. In their study population, a lipase level just above the upper limit of normal (ie, > 209 U/L) was arbitrarily considered as abnormal (group 2) by the authors. Obviously, this approach will have included some of the clinical conditions mentioned above, in which mildly increased lipase levels of extrapancreatic origin also can be seen.

Thus considered, Manjuck and colleagues found increased lipase levels in 40% of critically ill patients on ICU admission. Reasonably, renal insufficiency as a source of hyperlipasemia of extrapancreatic origin was a criterion to exclude patients from the study, but possibly group 2 may have selected patients with alcohol abuse or liver disease whose lipase levels could be raised at the baseline. Interestingly, there was no difference in the incidence of history of alcohol abuse between groups, but transaminase levels were found to be significantly increased in group 2.

In their study, Manjuck et al have identified hypotension, fever, low hemoglobin levels, elevated bilirubin levels, and the need for mechanical ventilation as determinants of higher lipase levels among critically ill patients at ICU admission. Because patients with mildly increased lipase plasma levels were pooled with others having much higher levels, including several cases of confirmed pancreatitis, perhaps multivariate logistic regression analysis may be of limited value in order to predict significant hyperlipasemia. However, good agreement is expected between these variables and abnormal values of lipase at any level.

In the report by Manjuck et al, imaging studies were performed in 50% of patients in group 2, possibly those with markedly increased lipase levels. CT scans or ultrasonographic imaging studies of the pancreas revealed positive findings in only 11 patients. However, these imaging methods may have some limitations in explaining mild increases in lipase levels that result from other conditions. More than 50% of cases of asymptomatic, mild elevations of serum lipase levels in the general population are found to be of pathoanatomic causes using magnetic resonance cholangiopancreatography (MRCP). (34) Mechanical alterations of the bile duct or the pancreas can possibly be better seen using this method. The "gold standard" endoscopic retrograde cholangiopancreatography carries a risk of morbidity and mortality, and, although other imaging methods such as endoscopic ultrasound, small-bowel follow through, or hepatobiliary scanning are also available, MRCP may be the preferred method. (28,34,35)

Reported findings from MRCP in such cases are pancreas divisum, primary sclerosing cholangitis, chronic pancreatitis, healed pancreatic laceration, juxtapapillary duodenal diverticulum, papillary sclerosis, intraductal pancreatic lithiasis, and hemochromatosis. (34) MRCP also has been used in clinical assessment after pancreatic trauma and provides useful information to guide management decisions. (28,35)

Thus, although in this report a minority of positive findings of imaging studies was found, other abnormalities possibly could have been detected by alternative methods in order to better explain the clinical significance of increased lipase levels on admission to the ICU. Although we agree with Manjuck and colleagues that common conditions in the critically ill, such as hypoperfusion, major surgery, and others, can be responsible for pancreatic damage that would explain increased lipase levels on ICU admission, other diagnoses or comorbidities also may be related to the minor lipase derangements that are observed among these patients.

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