GASTROENTEROLOGY

1992;103:1706-1711

CORRESPONDENCE Readers are encouraged to write Letters to the Editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence Section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.

Anti-Neutrophil Cytoplasmic Autoantibodies in Relatives of Patients With Ulcerative Colitis Dear Sir: We read with great interest the paper on anti-neutrophil cytoplasmic antibodies (ANCAs) in ulcerative colitis (UC) by Duerr et al.’ Since the initial observation by Targan et al. in 1989,’ the presence of ANCAs has been confirmed in the sera of patients with inflammatory bowel disease (IBD) with positive findings ranging from 23% to 86% in UC and from 0% to 20% in Crohn’s disease (CD) using indirect immunofluorescence (IIF). In a recent series of 238 patients with IBD we found ANCAs in 43 of 90 patients with UC (48%) and in 10 of 148 patients with CD (7%).3 A recent report stating that ANCAs were found in 15.7% of healthy relatives of patients with UC, thus suggesting that ANCAs may be a marker of genetic susceptibility,4 prompted us to search for ANCAs in 30 patients with UC, 91 first-degree healthy relatives, and 9 second-degree healthy relatives to try to confirm this hypothesis. Twenty-six families in northern France were studied. Twentyone had 1 member with UC and 73 first-degree and 8 second-degree parents. Five other families had 2 members with inflammatory bowel disease (4 families had 2 with UC and 1 family had 1 with UC and 1 with CD) and 18 first-degree parents and 1 seconddegree parent. The control group included 60 healthy blood donors and 10 spouses of patients with UC. Determination of presence of ANCAs was performed using IIF according to the guidelines of the first international workshop on ANCA.’ All slides were assessed by two well-trained observers in a blinded fashion. Perinuclear ANCAs (p-ANCAs) were found in 15 of 30 patients (50%) with UC and 0 of 70 controls. None of the 91 first-degree and 9 second-degree relatives had p-ANCAs. Within the 4 families having 2 probands with UC, p-ANCAs were absent in both twice and present in one of the proband and absent in the other twice. Thus, in our series, p-ANCAs do not appear to be potential markers of genetic susceptibility to UC. This discrepancy with previous data4 may be related to the different genetic background of the two populations. D. REUMAUX, PH.D. L. DELECOURT, M.D. J. F. COLOMBEL, M.D. L. H. NOEL, PH.D. P. DUTHILLEUL, PH.D. A. CORTOT, M.D.

Laboratoire d’He’mato-Immunologie CH Valenciennes Service des Maladies de I’Appareil Digestif CHRU Lille and INSERM LJ 90 De’partement de Ndphrologie Ho^pitaI Necker Paris, France 1. Duerr RH, Targan SR, Landers CJ, Sutherland

2.

LR, Shanahan F. Anti-neutrophil cytoplasmic antibodies in ulcerative colitis: comparison with other colitides/diarrheal illnesses. Gastroenterology 1991;100:1590-1596. Targan S, Saxon A, Landers C, Ganz T, Shanahan F. Serum anti-neutrophil cytoplasmic autoantibodies distinguish ulcera-

tive colitis from Crohn’s disease patients (abstr). Gastroenterology 1989;96:505A. Colombel JF, Reumaux D, Duthilleul P, Noel LH, GowerRousseau C, Paris JC, Cortot A. Antineutrophil cytoplasmic auto-antibodies in inflammatory bowel disease (submitted). Shanahan F, Duerr R, Rotter J, et al. Neutrophil autoantibodies in ulcerative colitis: familial aggregation and genetic heterogeneity (abstr). Gastroenterology 1991;100:614A. Wiik A. Delineation of a standard procedure for detection of ANCA. APMIS 1989;97(Suppl 1):12-13.

Oral 4-Aminosalicylic Ulcerative Colitis

Acid Therapy in

Dear Sir: Ginsberg et al.’ report that oral 4-aminosalicylic acid (4-ASA) therapy is effective in the treatment of ulcerative colitis (UC) but that “the mechanism by which the aminosalicylates reduce inflammation in colitis is unknown.” We would like to suggest that the beneficial effect of salicylates in UC may be due to their anticoagulant action. We have reported a marked improvement in three patients with UC, poorly controlled on standard therapy, when treated with the anticoagulant heparin.’ On the basis of our results and the presence of fibrin thrombi in the mucosal blood vessels of our patients we have proposed a vascular thrombotic etiology for UC. This view is supported by the high incidence of thromboembolic events in patients with UC (traditionally viewed as complications) and by associated disorders such as pyoderma gangrenosum, toxic megacolon, and erythema nodosum, in which there is evidence of thrombosis leading to ischemia. Many of these “complications” predate the onset of UC and are not cured by colectomy, suggesting that they are not in fact complications but associated conditions sharing a common etiology, i.e., vascular thrombosis. Also, Wakefield et al. have reported evidence of vascular occlusion in the closely related condition of Crohn’s disease,3 and Lam et aL4 have shown a hypercoagulable state in patients with UC and Crohn’s disease. The etiology of UC has remained unknown despite years of intensive research, suggesting that a novel approach is required. We consider that the evidence for a vascular etiology is impressive, and this could explain why the salicylates, which exert an anticoagulant action by blocking the production of thromboxane A, ,’ have been shown to be of benefit in UC. PETER GAFFNEY, MCH., F.R.C.S. CUIMIN DOYLE, F.R.C.PATH. ANNE GAFFNEY, PH.D.

Mallow General Hospital County Cork and Cork Regional Hospital Cork, Ireland Ginsberg AL, Davis ND, Nochomovitz LE. Placebo-controlled trial of ulcerative colitis with oral 4-aminosalicylic acid. Gastroenterology 1992;102:448-452. Gaffney PR, O’Leary JJ, Doyle CT, Gaffney A, Hogan J, Smew F, Annis P. Response to heparin in patients with ulcerative colitis. Lancet 1991;337:238-239. Wakefield AJ, Sawyerr AM, Dhillon AP, Pittilo RM, Rowles PM, Lewis AAM, Pounder RE. Pathogenesis of Crohn’s disease:

November

CORRESPONDENCE

1992

multifocal gastrointestinal infarction. Lancet 1989;11:10571062. 4. Lam A. Borda IT, Inwood MJ, Thomson S. Coagulation studies in ulcerative colitis and Crohn’s disease. Gastroenterology 1975;68:245-251. 5. Majerus PW, Braze GJ Jr., Miletich JP, Tollefsen DM. Anticoagulant, thrombolytic and antiplatelet drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon, 1990:1311-1331.

RAUL A. MARINELLI,PH.D. Instituto de Fisiologr’a Experimental Facultad de Ciencias Bioqm’micas y Farmaceuticas Suipacha 570 2000 Rosario, Argentina 1.

2.

Bile Salt-Induced Biliary Excretion of Iron in Iron-Loaded Rats Dear Sir: I have read with interest the article by Levy et al.’ dealing with the influence of bile salts on the biliary excretion of iron in ironloaded rats. This article states that taurocholate (TC) and other choleretics can increase the biliary iron excretion in iron-loaded rats, The authors proposed three mechanisms to explain this finding: (a) the choleresis per se; (b) an association between bile salt micelles and iron; and (c) an association between bile salt monomers and iron. LeSage et al.’ have previously reported that in rats with iron overload excess iron is sequestered in hepatic lysosomes and that the biliary iron excretion from these organelles is an important excretory route for excess hepatic iron. Levy’s study confirms that under basal conditions the biliary iron in iron-loaded rats is derived from hepatocyte lysosomes. Nevertheless, it is clear that the authors did not consider the biliary access of iron via a bile saltstimulated lysosomal pathway as a fourth mechanism capable of explaining their results. On this subject, it should not be ignored that biochemical and morphological evidence from the literature indicate that bile salts can stimulate the output of lysosomal content into bile.3-8 Thus, the administration of TC to iron-loaded rats could stimulate the biliary discharge of iron-loaded lysosomes. This concept is supported by Levy et al’s own data, which indicate that the lysosomal inhibitor chloroquine abolished the TCinduced biliary iron excretion in iron-loaded rats. On the other hand, Levy’s study showed that TC failed in stimulating the biliary lysosomal discharge in normal rats, although such a stimulation was clearly shown for iron-loaded rats. This discrepancy with the literature may be related to the enzyme selected in this study as lysosomal marker, because the N-acetyl+ glucosaminidase (NABG) has been reported to be inhibited by bile salts.‘Thus, it is possible that the increment in bile salt concentration due to TC infusion inhibited the enzyme activity, thus masking a true increase of its biliary excretion. The iron-loaded rats have an increased number of lysosomes in the pericanalicular area of the hepatocyte and a higher hepatic NABG activity.’ Moreover, it was also reported that under stimulated conditions (i.e., colchicine treatment], the iron-loaded rats show higher biliary output of lysosomal enzymes than normal rats.’ Therefore, a higher biliary NABG activity that might surpass the bile salt-induced inhibition can be expected under TC-stimulated conditions. Nevertheless, because in normal rats, unlike those with iron overload, hepatic iron is not localized in lysosomes,’ the increased biliary iron excretion during bile salt infusion necessarily implies mechanisms other than lysosomal discharge, such as those suggested by the authors. In conclusion, it seems very probable that the major mechanism determinant of the bile salt-stimulated biliary iron excretion in iron-loaded rats is an increased discharge of iron-loaded lysosomes into bile. Additional mechanisms such as those proposed by the authors should be taken into account, but their contribution appears to be less important.

1707

3.

4.

5.

6.

7.

8.

9.

Levy P, Dumont M, Brissot P, Letreut A, Favier A, Deugnier Y, Erlinger S. Acute infusions of bile salts increase biliary excretion of iron in iron-loaded rats. Gastroenterology 1991; 101:1673-1679. LeSage GD, Kost LJ, Barham SS, LaRusso NF. Biliary excretion of iron from hepatocyte lysosomes in the rat. A major excretory pathway in experimental iron overload. J Clin Invest 1986;77:90-97. Marinelli RA, Luquita MG, Rodriguez Garay EA. Bile salt-related secretion of acid phosphatase in the rat. Can J Physiol Pharmacol 1986;64:1347-1352, Marinelli RA, Carnovaje CE, Rodriguez Garay EA. Bile protein secretion in the rat estimulated by taurocholate: effect of chloroquine. Can J Physiol Pharmacol 1988;66:749-753. Marinelli RA, Carnovale CE, Rodriguez Garay EA. Biliary excretion of proteins in the rat during dehydrocholate choleresis. Can J Physiol Pharmacol 1990;68:1286-1291. Rahman K, Coleman R. Output of lysosomal contents and cholesterol into bile can be stimulated by taurodehydrocholate. Biochem J 1987;245:289-292. Le Sage GD, Baumgart MA, Robertson, WE. Bile acid-dependent secretion of lysosomal enzymes into rat bile (abstr). Hepatology 1987;7:1075. Le Sage GD, Lasater J, Baumgart MA, Robertson WE. Demonstration of bile acid-dependent vesicular transport by fluorescent microscopy (abstr). Gastroenterology 1989;96:1445. La Russo NF, Fowler S. Coordinate secretion of acid hidrolases in rat bile: hepatocyte exocytosis of lysosomal protein? J Clin Invest 1979;64:948-954.

Relationship Between Colorectal Neoplasia and Primary Sclerosing Cholangitis in Ulcerative Colitis Dear Sir: We have read the recent article by Broome et al.’ with great interest. As well outlined in the accompanying editorial by Hansuer,’ several report?’ from studies of primary sclerosing cholangitis (PSC) suggest that the risk for colorectal neoplasia may be increased in patients with ulcerative colitis (UC) and PSC. Unfortunately, these studies were limited by the small number of patients with such a complication. In fact, we were able to identify from the literature’~3-‘o fewer than 30 cases of colorectal carcinoma complicating UC and PSC. To help elucidate this potential relationship, we retrospectively reviewed our Lahey Clinic experience. An interim review of patients enrolled in our prospective surveillance program” for long-standing UC showed 5 patients with PSC among 204 cases available for analysis. Of 45 patients with neoplastic findings, 2 patients had PSC (l/22 colorectal carcinoma, O/l1 high-grade dysplasia, and l/12 low-grade dysplasia). In comparison, 3 patients had PSC in the remaining group without any evidence of neoplastic change in the colon. In contrast to the study by Broome et al.,’ the rates of PSC in the two groups were not statistically different (P = 0.38). Conversely, we reviewed the risk of colorectal carcinoma among 159 patients with PSC seen between 1957 and 1988. Of a total of 920,612 patients seen during this period, 5092 patients had colorectal carcinoma. A total of 2211 patients had UC, and 43 patients had associated colorectal carcinoma. Among the 62 pa-