Diagnosis of chronic pancreatitis

December

CORRESPONDENCE

1985

ic fluid that is chemically similar to the one described by us in the dog (5). This factor enhanced the antibacterial activity of several antibiotics, most of which act primarily or secondarily on the bacterial ribosome, the presumed site of action of the canine pancreatic factor. We share with Gyr et al. the feeling that this topic deserves further work.

E. RUBINSTEIN,M.D. Infectious Diseases Unit Chaim Sheba Medical Center Tel-Hashomer 52621,Israel 1. Gvr K, Felsenfeld 0, Zimmerli-Ning M. Effect of oral pancreatic enzymes on the course of cholera-in protein-deficient vervet monkeys. Gastroenterology 1978;74:511-3. Gyr K, Felsenfeld 0, Zimmerli-Ning M. The effect of oral pancreatic enzymes on the intestinal flora of protein-deficient vervet monkeys challenged with Vibrio cholerae. Am J Clin Nutr 1979;32:1592-6. Gyr K, Felsenfeld 0. The effect of oral pancreatic extract on jejunal bactericidal activity in protein-deficient vervet monkeys challenged with Vibrio cholerae. Acta Trop (Base])

1979;36:147-50. Mett H, Gyr K, Zak 0, Vosbeck K. Duodeno-pancreatic secretions enhance bactericidal activity of antimicrobial drugs. Antimicrob Agents Chemother 1984;26:35-8. Rubinstein E, Mark Z, Haspel J, et al. Antibacterial activity of the pancreatic fluid. Gastroenterology 1985;88:927-32.

Opisthorchis

viverrini

Infection

and

Cholangiocarcinoma Dear Sir: Kurathong and coworkers (1) clarify the relationship between hepatobiliary cancer and Opisthorchis viverrini infection in northeastern Thailand, a region where this fluke is endemic. It appears that 12 of 13 hepatobiliary tumors were found in subjects with documented fluke infestation; by comparison the infection rate in the noncancer population was 79%, giving a relative risk of 4.9. The authors state that the intensity of infection does not correlate with the risk of cholangiocarcinoma (CCC) and that duration of infection may be a more important determinant. Yet from their own data there is a hint that intensity of infection may indeed be related to CCC. In their report the male to female ratio for CCC was 2.4:1(10 of 321 men vs. 3 of 230 women in their sample had CCC). One can compare the intensity of infection in men and women by dividing the mean male egg count in the stool (24.82) by the mean value for females (10.62). The resulting ratio (2.3) is rather similar to the male/female case ratio. Thus heavier rates of infestation could be one explanation for the observed excess of men with CCC in the study. For some human cancers incidence is determined by both dose and exposure time, with exposure time the more important parameter. (2). With additional information, such as age-specific incidence rates for CCC, it might be possible to develop a model for this cancer that relates incidence of the tumor to duration and intensity of exposure to the putative risk factor.

ALBERT B. LOWENFELS. M.D. Professor of Surgery New York Medical College Valhalla, New York 10595

Kurathong S. Lerdverasirikul thorchis viverrini infection spective, case-controlled

1449

P. Wongpaitoon V, et al. Opisand cholangiocarcinoma. A pro1985;89: study. Gastroenterology

151-6. Doll R, Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidemiol Community Health 1978; 32:303-13. Reply. We are very grateful to Lowenfels for his interest in our paper, and for making what seems to be a more appropriate conclusion concerning the correlation between intensity of infection and cholangiocarcinoma [CCC). However, concerning the relative risk of 4.9, as calculated by Lowenfels, our data actually showed that all (not 12 as he stated) of the 13 patients with CCC (with or without hepatocellular carcinoma) had 0. viverrini demonstrated either in their feces (9 patients) or in the bile fluid aspirated from intrahepatic biliary trees (4 patients) (Table 3, p. 154). As there is no CCC in the uninfected patients, the relative risk therefore is incalculable.

SUCHA KURATHONG, M.D.,D.T.M.H. Chief Division of Gastroenterology Ramathibodi Hospital Bangkok, Thailand 10400

Diagnosis

of Chronic

and

Tropical

Medicine

Pancreatitis

Dear Sir: Niederau and Grendell in their recent review on the diagnosis of chronic pancreatitis (1) misrepresent the serologic diagnosis of this disease. In describing the radioimmunoassay to the serum trypsinogen [also called trypsinlike immunoreactivity), they dismiss this test’s diagnostic capabilities by stating that this test has been shown to “miss all patients without steatorrhea.” They then go on to mistakenly list causes of “false-positive” elevations for this marker (e.g., acute pancreatitis, pancreatic pseudocysts, acute exacerbations of chronic pancreatitis, chronic renal failure). A “positive” serum trypsinogen for chronic pancreatitis is demonstrated by a low level of this enzyme. The above-listed conditions raise a lowered trypsinogen level into the normal or elevated range, leading to false-negative, not false-positive, determinations. The strength of the serum trypsinogen test is, in fact, its lack of false-positives (i.e., it has excellent specificity). We have recently reviewed the literature on this subject and have found that the sensitivity of this assay in diagnosing chronic pancreatitis with steatorrhea is 85% and without steatorrhea is 30% (2). The specificity for this assay is >98% (2). The only condition other than chronic exocrine pancreatic disorders (chronic pancreatitis, cystic fibrosis, cancer of the pancreas] that has been reported to give low serum trypsinogen levels is primary diabetes mellitus. Using the German-produced serum trypsinogen assay (RIA Gnost), several European groups have reported low levels of serum trypsinogen in a significant number of patients with primary diabetes mellitus. We have been unable to confirm this finding in our study using the Italian-produced trypsinogen assay (CIS Trypsik, distributor Syncor Corp.. Sylmar, Calif.) in which only 3 of 37 patients with diabetes mellitus had a low trypsinogen level, all 3 of whom also had concomitant chronic pancreatitis (3). We, therefore, consider the serum trypsinogen test to be the most specific of the noninvasive tests to diagnose chronic pancreatitis. The ideal test should be easily available, cheap, simple to perform, risk-free to the patient, and offer a high degree of sensitivity and specificity. The three noninvasive tests available in the United States at the present time to diagnose chronic

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-