Diagnosis of chronic pancreatitis

1450

Table

GASTROENTEROLOGY

CORRESPONDENCE

1. Comparison

of Three

Noninvasive

Tests

for the

CP, chronic

of Chronic

Pancreatitis

Bentiromide

x-ray of abdomen

85’s (2)

71% (1)

65% (4)

30% (2)

46% (1)

98% (21 Special order

8Ou/u-90% (1) Special order

96% (4) Everywhere

$50

560 Minimal Simple

Trypsinogen Sensitivity (severe CP) Sensitivity (mild CP) Specificity Availability cost Risk to patient Ease of use

Diagnosis

Vol. 89, No. 6

$30

None Very simple

Probably none Mildly cumbersome

27% (4)

pancreatitis

pancreatitis are the flat plate x-ray of the abdomen. the serum trypsinogen assay, and the urinary bentiromide test (also called Chymex or nBT-PABA test]. I have ranked these three tests in Table 1. The serum trypsinogen is the simplest, cheapest. and possibly the most accurate of the noninvasive diagnostic tests. If it can be easily obtained, it is reasonable that the trypsinogen assay be used as the initial diagnostic test of choice or in combination with the bentiromide test or flat plate of the abdomen. WILLIAM

M. STEINBERG, M.D.

Division of Gastroenterology George Washington University Washington.

Medical

Center

D.C. 20037

Niederau C. Grendell C. Diagnosis of chronic pancreatitis. Gastroenterology 1985:88:1973-95. Steinberg WM, Anderson KK. The serum trypsinogen in the diagnosis of chronic pancreatitis. Dig Dis Sci 1984;29:988-93. Steinberg WM, Goldstein SS, et al. Predictive value of a low serum trypsinogen. Dig Dis Sci 1985;30:547-51. Guien C. Radiological examination of the pancreas. In: Howat HT. Sarles H, ed. The exocrine pancreas. London: WB Saunders, 1979:186.

Dear Sir: (1). The progress article on the diagnosis of chronic pancreatitis which I have studied with interest, is a good comprehensive review on this topic. However, there are two important problems on which I would like to comment, namely, (a) “early” or “mild” chronic pancreatitis and (b) “staging” of the disease. “Early” or “mild” chronic puncreatitis. This term, repeatedly used in the review and in the literature, lacks a precise definition. Pancreatic exocrine insufficiency can be classified arbitrarily from “mild” to “severe.” However, mild to severe exocrine insufficiency is not identical with mild to severe chronic pancreatitis, particularly because pancreatic insufficiency of various extent and for variable duration is known to occur in postacute states of pancreatitis (2-5) and in asymptomatic chronic alcoholics (6). Thus “mild” or “early” chronic pancreatitis can be suspected, but because of the lack of a gold standard (except histology of a large specimen) it cannot be diagnosed. Much of the confusion in the literature regarding function or morphologic tests results from overinterpretation of such data in terms of chronic pancreatitis. Sequential function studies are necessary to differentiate acute (reversible) and chronic (progressive) pancreatic damage. However, the term “early stages” of chronic pancreatitis (in contrast to advanced disease) cannot be dismissed. It will be used also in this letter for classification (retrospectively) of early phases of the disease in patients with proven chronic pancreatitis. Pancreatography has recently been suggested as gold standard of chronic pancreatitis (7). This thesis has not as yet been validated. It is generally accepted that advanced chronic pancre-

atitis is associated with typical marked ductal changes. It is probably an oversimplification, however, to interpret mild to moderate ductal changes in terms of mild to moderate chronic pancreatitis. Ductal changes of variable extent may be observed in elderly patients and in postacute states of pancreatitis (2). Thus the diagnostic accuracy of pancreatography for “early” chronic pancreatitis remains to be proved. In alcoholic chronic pancreatitis there is a striking interrelationship of clinical pattern, functional impairment, and morphologic changes (3,8), and therefore any situation with a marked dissociation between these features should be interpreted with caution in terms of chronic pancreatitis. “Staging” of chronic pancreatitis. Pain is a major therapeutic problem of chronic pancreatitis. As the pathomechanisms of pain are ill-defined, the therapeutic approach is empirical (and symptomatic) and has to be based on an accurate diagnostic staging of the disease by analyzing the four important factors that determine the natural course of pancreatitis. namely, etiology. clinical pain pattern, morphology, and function. Chronic pancreatitis is not a well-defined uniform disease entity, but it is a dynamic (progressive) process with a changing pattern of the latter three factors. These factors are closely interrelated and evolve from onset to advanced stages of the disease (8). Three typical clinical patterns that can be correlated to functional and structural alterations can be distinguished. Early stages are usually characterized by recurrent, shortlasting episodes (57 days) of “acute” pancreatitis. A definite classification into “relapsing acute” and “chronic relapsing” pancreatitis is hardly possible at onset of the disease. Prevention of recurrences depends on the detection (and exclusion) of the etiologic factor(s). Advanced uncomplicated chronic pancreatitis is characterized by the absence of pain, marked impairment of pancreatic function (e.g., diabetes, steatorrhea), and often by the appearance of pancreatic calcifications (8). Local complications, in particular pseudocysts or partial extrahepatic obstruction, with or without cholangitis, may ocr_ur in early or late stages of the disease. Clinically, long-lasting and often severe pain (>lO days] or recurrent pain episodes at short intervals are suggestive evidence for local complications (8). Morphologic methods like ultrasound, computed tomography. and endoscopic retrograde cholangiopancreatography are important for diagnostic workup. Surgery, particularly drainage procedures, will relieve the severe pain related to the local complication. However. postoperative recurrences of shortlasting pain episodes are likely to occur in early stages of chronic pancreatitis, especially when alcohol abuse is continued (8). On the other hand, prompt and lasting pain relief is generally observed postoperatively in patients with advanced chronic pancreatitis and despite continued alcohol abuse (8). Thus in our experience, accurate “staging” of chronic pancreatitis preoperatively or postoperatively. analyzing both func-

December

CORRESPONDENCE

1985

bon and morphology, is of diagnostic and prognostic relevance, particularly in patients with severe pain. Persistent severe pain, probably related to ductal hypertension [in the absence of local complications), is another, less common condition in chronic pancreatitis (8). Sequential function studies for “staging” of chronic pancreatitis are also important in these patients as the secretory pressure (and ductal hypertension) will diminish in association with progressive atrophy of acinar tissue (and marked exocrine insufficiency). In summary, the morphologic tests as advocated as primary diagnostic tools for the rational diagnostic approach of chronic pancreatitis (see Reference 1, Figure 1) are very valuable for detection of pancreatic cancer and of local complications of chronic pancreatitis. For diagnosis and “staging” of chronic pancreatitis, sequential function studies in combination with the morphologic tests (and patience] will yield clinically relevant information, and thus form the basis for a rational approach to diagnosis, therapy, and prognosis of chronic pancreatitis. RUDOLF W. AMMANN,

M.D.

Division of Gastroenterology Department of Medicine University Hospital of Zurich Riimistrusse 100 CH - 8091 Zurich, Switzerland 1. Niederau 2.

3.

4.

5.

6. 7.

8.

C, Grendeil JH. Diagnosis of chronic pancreatitis. Gastroenterology 1985;88:1973-95. Angelini G, Pederzoli P, Caliari S, et al. Long-term outcome of acute necrohemorrhagic pancreatitis. Digestion 1984;30:131-7. Gyr K, Toskes P. Pancreatic function testing. In: Gyr K. Singer MV, Sarles H, eds. Pancreatitis-concepts and classification. Amsterdam: Excerpta Medica, 1984:329-35. Mitchell CJ. Playforth MJ, Kelleher J. McMahon MJ. Functional recovery of the exocrine pancreas after acute pancreatitis. Stand J Gastroenterol 1983:18:5-8. Ammann RW, Akovbiantz A, Hacki W, et al. Diagnostic value of the fecal chymotrypsin test in pancreatic insufficiency, particularly chronic pancreatitis. Digestion 1981;21:281-9. Diirr HK. Alkoholschadigung des Pankreas. Internist 1978: 19:123-30. Axon ATR, Classen M, Cotton P, et al. Pancreatography in chronic pancreatitis: international definitions. Gut lY84;25: 1107-12. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Gastroenterology 1984: 86:820-8.

Reply. We thank Ammann for his kind remarks about our article (1) and for his thoughtful comments, which reflect his expertise and extensive experience in caring for patients with chronic pancreatitis. We also share his opinion that the terms “early” or “mild” chronic pancreatitis lack precise definition, which has made studies in this area difficult to compare. However. we believe that these terms do have some validity and usefulness in describing an early stage in the natural history of many patients with chronic pancreatitis, during which pain is often the predominant feature and exocrine or endocrine insufficiency as well as severe abnormalities of the pancreatic ducts have yet to develop. It is at this stage when an imaging study, pancreatic function test, or serum enzyme determination capable of reliably confirming the clinical diagnosis of chronic pancreatitis as the likely cause of pain would be most helpful. Following this “early” stage of chronic pancreatitis, many patients will develop calcifications and frank exocrine or endocrine insufficiency (often accompanied by a reduction in pain] (2) as well as progressively more severe

1451

abnormalities of the pancreatic ducts (3). At this “late” stage the diagnosis is often reasonably certain on clinical grounds without the contribution of other diagnostic studies. Although some indirect tests of pancreatic function are useful in following the progression of pancreatic insufficiency (“staging” chronic pancreatitis), we are not convinced that a clinician can reliably use these tests to determine the need for and timing of surgical interventions for the treatment of either chronic pain or complications such as pseudocysts or biliary obstruction in chronic pancreatitis. We thank Steinberg for pointing out an error in our article (1) where the term “false-positive” is used to describe normal or elevated serum trypsinogen levels produced by conditions such as acute pancreatitis, pseudocysts, or chronic renal failure in patients with chronic pancreatitis. These, of course, are actually “false-negative” results for this assay because a “positive” result for chronic pancreatitis is a serum trypsinogen concentration below the normal range. However, we believe that we did not “misrepresent the serologic diagnosis of this disease” (chronic pancreatitis) as Steinberg alleges. Rather, he has greatly overstated the case for the use of the serum trypsinogen assay in the diagnosis of chronic pancreatitis. In his recent review (4) Steinberg calculated that the serum trypsinogen assay can diagnose advanced chronic pancreatitis with a sensitivity of 85% and mild-to-moderate chronic pancreatitis with a sensitivity of 30%. Even if one accepts these figures, it is generally not a difficult problem to diagnose chronic pancreatitis in an advanced stage when steatorrhea and diabetes are present, but it is a major challenge to diagnose the disease earlier in its course. We doubt that a test with a sensitivity of 30% will be helpful in the cases that cause the physician the greatest difficulty. Furthermore Steinberg’s review capabilities of serum trypsinogen reasons:

(4) overestimates the diagnostic measurement for the following

First, Steinberg omitted both from his review and from his letter three studies reporting the lowest sensitivities for the serum trypsinogen assay: i.e., 24% as reported by Borgstrom and Wehlin (51, 32% as reported by Enslev et al. (6). and 33% as reported by Heinrich et al. (7). These results for sensitivity include patients with severe chronic pancreatitis. Two of these studies differentiate between mild-to-moderate and severe disease and report sensitivities for mild-to-moderate disease of 10.5% (5) and 12.5% (6). This extremely low sensitivity is in agreement with three other studies that reported that all patients with mild-to-moderate disease were missed by measurement of serum trypsinogen (810). Second, Steinberg differentiates the patients reported by Koop et al. (11) into groups with mild-to-moderate and with severe disease. The authors of this study themselves do not make this differentiation for all patients and do not provide sufficient data to do so. Steinberg calculates far this study a sensitivity of 68.3% for mild-to-moderate pancreatitis and 85.7% for severe disease (4). Both values, however, exceed the sensitivity of 65% which the authors of this study calculated for the entire group of patients with chronic pancreatitis of all degrees of severity. This suggests that Steinberg’s differentiation of this patient sample into groups based on severity leads to an inaccurately high estimate of sensitivity. Third. Steinberg includes in his review (4) an older study by Fahrenkrug and Magid (12) showing a very good sensitivity of 93%] for their patients with chronic pancreatitis. However. this same group of investigators from the same hospital have published a more recent article (6) in which they report a sensitivity of only 40%~ for the serum trypsinogen assay in patients with chronic pancreatitis of all grades of severity. This latter article was not included in Steinberg’s review. Fourth, Gullo et al. (8) mention that 9 of 12 patients with severe