788 Gut 1996; 38: 788-791

CASE REPORT

Interchange between collagenous and lymphocytic Gut: first published as 10.1136/gut.38.5.788 on 1 May 1996. Downloaded from in severe disease with autoimmune associations requiring : a case report

T E Bowling, A B Price, M Al-Adnani, P D Fairclough, N Menzies-Gow, D B A Silk

Abstract report a case of following Background-Collagenous colitis and a fulminant course necessitating emergency present with a similar colectomy, demonstrate the lability ofthe colla- clinical picture. Whether these conditions gen plate, and the common ground between are separate entities or whether they collagenous and lymphocytic colitis. represent different pathological stages of the same condition is an unresolved issue. Patient-This is a case of collagenous Case report colitis following a fulminant course in A 46 year old white woman was referred in which a colectomy was necessary. In the December 1992 with a three month history of operative specimen the thickened collagen persistent diarrhoea after a course of amoxy- plate, which had been present only two cillin for an upper respiratory tract infection. weeks preoperatively had been lost and Ten years previously she had been investigated the pathology was ofa lymphocytic colitis. for diarrhoea with a barium , barium Six months postoperatively this patient meal, and jejunal . No diagnosis was developed a CREST syndrome and made, and a few months later the diarrhoea primary biliary . stopped spontaneously. There was no other Conclusions-This case shows the relevant past medical history. At the initial con-

lability http://gut.bmj.com/ of the collagen plate and the common sultation all her blood tests were normal, but ground between collagenous and lympho- three day faecal weights were abnormal at 271 cytic colitis, and presents evidence that g/day (normal <200). Faecal fat was normal, these two conditions are different mani- stool cultures for enteric pathogens and festations of the same disease. It also Clostridium difficile toxin were negative. A Department of describes for the first time an association was macroscopically normal, but and

Nutrition between collagenous colitis and CREST biopsy specimens showed clear evidence of a on September 26, 2021 by guest. Protected copyright. T E Bowling syndrome and primary biliary cirrhosis. diffiuse collagenous colitis (Fig 1). She was given D B A Silk (Gut 1996; 38: 788-791) salazopyrine (1 g three times a day) and and Histopathology prednisolone (10 mg/day), and for the next six M Al-Adnani Keywords: collagenous colitis, lymphocytic colitis, weeks her symptoms gradually improved. In interchange, colectomy, autoimmunity. early February 1993, however, she became Central Middlesex Hospital, London acutely unwell with a fever, severe diarrhoea, and cramping abdominal pains. Her blood Department of Collagenous colitis and lymphocytic colitis are results were normal, except for a neutrophil leu- Cellular Pathology, Northwick Park recently described inflammatory disorders of cocytosis of 18*5X109/1 (normal <11X109/1), Hospital, Harrow, the colon.1 2 Clinically, they are characterised and her faecal weights had increased to 374 Middlesex by a history of fluctuating watery diarrhoea but g/day (Fig 2). Plain abdominal x ray showed A B Price with normal appearances at barium enema and Department of colonoscopy. The clinical course of both con- Gastroenterology, St ditions is benign and there has not been, to Bartholomew's our knowledge, any report of either condition Hospital, London P D Fairclough following a fulminant course necessitating colectomy.3 They do differ in certain histologi- Department of cal abnormalities, most notably the thickened Gastroenterology, Princess Grace subepithelial collagen plate that occurs in Hospital, London collagenous but not lymphocytic colitis,4 but N Menzies-Gow in both a raised number of intraepithelial D B A Silk lymphocytes has been reported.4 This last fact Correspondence to: and the uneven distribution of the collagen Dr D B A Silk, Department of Gastroenterology and plate both within any series ofbiopsy specimens Nutrition, Central Middlesex and between interval series has led to consider- Hospital NHS Trust, London NW10 7NS. able debate whether these are two separate Figure 1: A phosphotungstic acid stain shozvs the thickened Accepted for publication conditions, or whether they represent different collagen plate ofup to 25 ,um, which is accompanied by a 9 November 1995 stages of the same disease process.4-11 We low grade colitis in the underlying . Collagenous and lymphocytic colitis in severe disease 789

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-fi1er 20 25 - 2 7 12 17 22 27. 1. Dmbe -Marh Apri ul - F u - 1 Figure 2: Clinical course chartingfaecal weights, temperature, and count. evidence of a total colitis. The macroscopic appearances at a second colonoscopy showed mild patchy inflammation with loss of the vascular pattern throughout the colon (Fig 3). Biopsy specimens again showed an active total collagenous colitis and inflammation extended into the terminal . She improved slowly Figure 4: The colectomy specimen with no gross with high doses of (40 mg abnormality visible. (The mucosal defects are the sitesfrom prednisolone/day), (100 mg/day), which microscopy blocks were selected.) and salazopyrine (1 g three times a day) and was discharged in late February. Four weeks were unremarkable (Fig 4). Extensive sam- later she again became acutely unwell with a pling only showed focal areas with a raised fever, and plain abdominal x ray again showed intraepithelial lymphocyte count of up to 40 a total colitis and mucosal oedema with no per 100 epithelial cells (normal <5) super- http://gut.bmj.com/ intestinal dilatation. Her white cell count was imposed on a background count of 14-18 per 17x109 and faecal weights 745 g/day. All her 100 epithelial cells. Occasional branched other blood tests, including erythrocyte sedi- crypts, indicative of previous damage, were mentation rate and albumin remained normal. present (Fig 5). Neither a thickened collagen A rectal biopsy at this time showed non- table nor signs of a severe colitis were specific inflammatory changes only with no seen. Postoperatively she made an excellent features ofcollagenous colitis. On this occasion recovery, and had her reversed in on September 26, 2021 by guest. Protected copyright. she did not respond to medical treatment, and July 1993. The intraepithelial surface lympho- remained acutely unwell with profuse diar- cyte count in the at the time of reversal rhoea, fever, abdominal tenderess, and leuco- was still above normal at 15-20 per 100 epithe- cytosis. She therefore underwent an emergency lial cells. The ileal count was normal. colectomy and ileostomy. At surgery the From a gastrointestinal point of view she serosal surface of the colon was hyperaemic remained well, but six months after the but, unlike that to be expected of an acute pan- ileostomy was reversed it was noted that her colitis, the macroscopic appearance of the wall y-glutamyltransferase and alkaline phos- and the mucosal surface of the resected colon phatase were marginally increased. In addition she was complaining of arthralgia, myalgia, dry

Figure 3: Colonoscopy appearances in the terminal ileum * '! (top right), caecal pole (top left), ascending colon (bottom Figure 5: Microscopyfrom the colectomy illustrates a raised right), and hepaticflexure (bottom left). The colon is intraepithelial lymphocyte count (about 40 of 100 diffusely abnormal with loss ofvascular pattern and colonocytes) but no other abnormality, in particular no granularity. residual evidence of a thickened collagen plate. 790 Bowling, Price, Al-Adnani, Fairclough, Menzies-Gow, Silk

eyes, and cold fingers and toes, and on exami- to diarrhoea.'9 Nevertheless, the differences in nation she had developed multiple telan- sex ratio, HLA phenotypes, and the absence of giectasia. Investigations showed a highly collagen table thickening in some well docu- positive antinuclear antibody titre, anticentro- mented cases of lymphocytic colitis lead mere antibodies, and antimitochondrial anti- groups to argue that the two conditions are

bodies with a titre of 1:1280. Her rheumatoid separate entities that rarely overlap.9-11 13 Gut: first published as 10.1136/gut.38.5.788 on 1 May 1996. Downloaded from factor was negative and a Schirmer's test was Recently 14 patients with collagenous colitis dry. It was concluded, therefore, that she had a were followed up with sequential , and mild version of the CREST syndrome and was these confirmed the patchy nature of the con- developing primary biliary cirrhosis. dition and that collagen plate thickening can wax and wane.20 In addition, it was com- mented that during resolution of collagen plate Discussion thickening the histological appearances did Collagenous colitis was first described in 19761 resemble those of a lymphocytic colitis.20 and in 1980.2 Lymphocytic In general, the natural history of both col- colitis, thought by some to be a more appro- lagenous and lymphocytic colitis is benign, priate term for the latter, was introduced in although the diarrhoea may be incapacitating.3 1989.4 Since these original reports more than At present no established treatment can effec- 230 cases of collagenous colitis'2 and 50 oflym- tively control the disease in all cases on a long phocytic colitis have been described.2 6 13 14 term basis and, although remissions of the These two conditions have many features in disease and disappearance ofthe collagen band common. Both present with cramping abdomi- have been described,5 2022 relapse of both nal pain and watery diarrhoea, caused by symptoms and histological abnormalities is decreased colonic fluid absorption.14-16 In both common.23 24 Recently it has been shown that the colon appears normal at colonoscopy and diverting the faecal stream results in the disap- on barium enema, and in both the diagnosis can pearance of the collagen plate, suggesting a only be made by biopsy. Differences between luminal toxin may have an aetiological role.25 the two include a smaller female predominance An association between antibiotic treatment in lymphocytic colitis4; an increase in HLA Al and collagenous colitis has been suggested26 and DRw 53, and a decrease in HLA A3 phe- but the exact relation between the two has not notypes in lymphocytic colitis'3 17 (there are no been clarified. In this case the patient had changes in HLA phenotype in collagenous received antibiotics briefly prior to the onset of colitis from the normal population'7). There are symptoms, so it is of course possible that this also differences in histological appearance. The may be ofrelevance to the genesis ofher colitis. presence of increased intraepithelial lympho- We, however, do not feel that the colitis in this cytes, often above 20 per 100 epithelial cells case was either an antibiotic associated colitis http://gut.bmj.com/ (normal <5), is mandatory to the diagnosis of or an infectious (self limiting) colitis. Repeated lymphocytic colitis, but it can accompany colla- stool cultures for pathogens and Clostridium genous colitis.4 11 There were an average of 14 difficile toxin were negative, and from the lymphocytes per 100 epithelial cells in the two pathology point of view the picture in this case presenting colonoscopic series, the predomi- was unlike either. The neutrophil and crypt nant cell being the neutrophil polymorph, patterns were unlike self limiting colitis, and on September 26, 2021 by guest. Protected copyright. reflecting the severity of the colitis at these neither self limiting nor antibiotic associated times. Obviously in collagenous colitis there has colitis have a collagen band. In addition, both to be a thickened subepithelial collagen table, clinically and endoscopically these were not with widths greater than 7-10 [i generally appropriate diagnoses. regarded as significant.1' 18 There is also Different coexisting diseases have been reported to be greater eosinophilic infiltration4 described in association with collagenous and and increased surface epithelial damage in col- lymphocytic colitis, including polyarteritis,26 lagenous colitis than in lymphocytic colitis.4 seronegative ,'3 27 ,6 28331 However, as the abnormality of collagenous small bowel villous atrophy unresponsive to colitis can be restricted to the right colon, be gluten withdrawal,6 13 32 pulmonary fibrosis,33 intermittently present and, as stated, be accom- Raynaud's disease,34 and .'0 13 34 panied by a raised intraepithelial lymphocyte There is, however, no consistent association count during its natural history, a watertight dis- with these disorders, although a common tinction between the two entities will require the autoimmune aetiology remains a possibility.35 prolonged study of appropriate patient groups We are unaware of any reported associations or the identification of distinct aetiologies. between scleroderma or primary biliary cirrhosis To date some groups have reported histo- and collagenous or lymphocytic colitis. logical progression from lymphocytic to col- Because there are no reported cases of either lagenous colitis5-8 and, along with the clinical collagenous or lymphocytic colitis pursuing a and histological similarities between the two fulminant course necessitating emergency conditions, subscribe to the view that they do colectomy, we wish to draw attention to a case represent the same disease. Other groups argue of a woman presenting with collagenous colitis, that if this was the case and lymphocytic colitis confirmed with colonoscopic biopsies on two did progress to collagenous colitis, there occasions, which did not settle with standard should be a correlation between collagenous medical treatment and, because of a deteriorat- colitis and the severity of diarrhoea - no such ing clinical condition, subsequently necessitated correlation has been found.'8 Moreover, a a colectomy. The perioperative serosal appear- thickened collagen plate does not always lead ance of the colon was of vascular congestion Collagenous and lymphocytic colitis in severe disease 791

8 Jessurun J, Yardley JH, Lee EL, Vendrell DD, Schiller LR, only, perhaps surprising in the light of the Fordtran JS. Microscopic and collagenous colitis: clinical features. An additional anomaly was different names for the same condition? Gastroenterology erythrocyte sedi- 1986; 91: 1583-4. the persistence of a normal 9 Yardley JH, Lazenby AJ, Giardiello FM, Bayless TM. mentation rate and serum albumin in a patient Collagenous, 'microscopic', lymphocytic, and other Perhaps these more subtle forms of colitis. Hum Pathol 1990; 21: with torrential diarrhoea. 1089-91.

features show that continuing conservative 10 Widgren S, Jlidi R, Cox N. Collagenous colitis: histologic, Gut: first published as 10.1136/gut.38.5.788 on 1 May 1996. Downloaded from morphometric, immunohistochemical and ultrastructural treatment in similar circumstances, despite studies: Report of 21 cases. Virchows Arch (A) 1988; 413: failing medical treatment, may be appropriate. 287-96. the dramatic lability 11 Bogolometz WV, Flejou JF. Newly recognised forms of This case also illustrates colitis: collagenous colitis, microscopic (lymphocytic) of the collagen abnormality. After extensive colitis, and lymphoid follicular . Semin Diagn mild Pathol 1991; 8: 178-89. sampling of the entire colon only a 12 Lindstrom CG. Collagenous colitis: an updating. Pathol Res increase in intraepithelial lymphocytes was Pract 1989; 185: A90. table 13 Giardiello FM, Lazenby AJ, Bayless TM, Levine EJ, Bias shown with no thickening of the collagen WB, Ladenson PW, et al. Lymphocytic (microscopic) whatsoever. It clearly shows that both the col- colitis. Clinicopathologic study of 18 patients and com- colitis can parison to collagenous colitis. Dig Dis Sci 1989; 34: lagen and the colitis of collagenous 1730-8. wax and wane over short periods of time, and 14 Bo-Linn GW, Bendrell DD, Lee E, Fordtran JS. An the be inde- evaluation of the significance of microscopic colitis in the pathogenesis of diarrhoea may patients with chronic diarrhoea. Jf Clin Invest 1985; 75: pendent of both, as suggested by the colonic 1559-69. secretion shown during in vivo perfusion 15 Loo FD, Wood CM, Soergel KH, Komorowski RA, Cheung H, Gay S, et al. Abnormal collagen deposition studies. 16 Collagen is usually regarded as stable and ion transport in collagenous colitis. Gastroenterology natural history of col- 1985; 88: A1481. and its lability during the 16 Rask-Madsen J, Hansen MGJ, Bukhave K, Scient C, lagenous colitis, in particular in this case where Henrik-Nielson R. Colonic transport of water and it was rapid and complete, is puzzling. electrolytes in a patient with secretory diarrhoea due to collagenous colitis. Dig Dis Sci 1983; 28: 1141-6. Collagen types I and III have been shown in 17 Giardiello FM, Lazenby AJ, Yardley JH, Bias WB, Johnson 36 with type IV being J, Alianiello RG, et al. Increased HLA Al and diminished the abnormal band21 HLA A3 in lymphocytic colitis compared to controls and restricted to the basal lamina. There is one patients with collagenous colitis. Dig Dis Sci 1992; 37: type IV deposited within the band.'5 496-9. report of 18 Lee E, Schiller LR, Vendrell D, Santa Ana CA, Fordtran JS. As far as we are aware, however, there have Subepithelial collagen table thickness in colon specimens been no studies on collagen turnover in col- from patients with microscopic colitis and collagenous colitis. Gastroenterology 1992; 103: 1790-6. lagenous colitis that allow speculation on an 19 Leigh C, Elahmady A, Mitros FA, Metcalf A, Al-Jurf A. metabolism as a mechanism for Collagenous colitis associated with chronic . increased AmJSurg Pathol 1993; 17: 81-4. these fluctuations. Finally, for the first time the 20 Carpenter HA, Tremaine WJ, Batts KP, Czaja AJ. between the pathology of collage- Sequential histologic evaluations in collagenous colitis: interchange correlations with disease behaviour and sampling strategy. nous colitis and lymphocytic colitis is seen in a Dig Dis Sci 1992; 37: 1903-9. colectomy specimen free of the sampling error 21 Jessurun J, Yardley JH, Giardiello FM, Hamilton SR,

Bayless TM. Chronic colitis with thickening of the sub- http://gut.bmj.com/ inherent in the existing studies in the literature. epithelial collagen layer (collagenous colitis): histologic It the picture and findings in 15 patients. Hum Pathol 1987; 18: 839-48. highlights overlapping 22 Gubbins GP, Dekovich AA, Ma CK, Batra SK. emphasises the difficulties faced in resolving Collagenous colitis: report of nine cases and review of the two distinct literature. South MedJ7 1991; 84: 33-7. the issue whether aetiologically 23 Bogolometz WV. Collagenous colitis. Curr Top Pathol 1990; diseases do exist. It is interesting that the 81: 219-27. lymphocyte count in this patient 24 Palmer KR, Berry H, Wheeler PJ, Williams CB, Fairclough intraepithelial P, Morson BC, et al. Collagenous colitis - a relapsing and was still raised at the time of ileostomy remitting disease. Gut 1986; 27: 578-80. showing a permanent 25 Jarnerot G, Tysk C, Bohr J, Eriksson S. Collagenous colitis on September 26, 2021 by guest. Protected copyright. revision, perhaps and fecal stream diversion. Gastroenterology 1995; 109: immunological defect. 449-55. described the first case 26 Giardiello FM, Hansen C, Lazenby AJ, Hellman DB, We have, therefore, Milligan FD, Bayless TM, et al. Collagenous colitis in of collagenous colitis necessitating, on clinical setting of non-steroidal anti-inflammatory drugs and anti- a colectomy and present evidence biotics. Dig Dis Sci 1990; 35: 257-60. grounds, 27 Giardiello FM, Bayless TM, Jessurun J, Hamilton SR, supporting the claim that collagenous colitis Bayless TM. Collagenous colitis: physiologic and are manifesta- histopathologic studies in seven patients. Ann Intern Med and lymphocytic colitis different 1987; 106: 46-9. tions of the same disease. We also have 28 O'Mahony S, Nawroz IM, Ferguson A. Coeliac disease and the first an association with collagenous colitis. Postgrad Med Jf 1990; 66: 238-41. described, for time, 29 Hamilton I, Sanders S, Hopwood D, Bouchier IAD. the CREST syndrome and primary biliary Collagenous colitis associated with small intestinal villous cirrhosis. atrophy. Gut 1986; 27: 1394-8. 30 Breen EG, Farren C, Connolly CE, McCarthy CF. Collagenous colitis and coeliac disease. Gut 1987; 28: 1 Lindstrom CG. 'Collagenous colitis' with watery diarrhoea 364-6. - a new entity? Pathol Eur 1976; 11: 87-9. 31 Eckstein RP, Dowsett JF, Riley JW. Collagenous entero- 2 Read NW, Krejs GJ, Read MG, Santa Ana CA, Morawski colitis: a case of collagenous colitis with involvement of SG, Fordtran JS. Chronic diarrhoea of unknown origin. the . Am Jf Gastroenterol 1988; 83: 767-71. Gastroenterology 1980; 78: 264-71. 32 Hwang WS, Kelly JK, Shaffer EA, Sylwestrowicz T, 3 Sloth H, Bisgaard C, Grove A. Collagenous colitis: a Klassen J. A novel with partial villous prospective trial of prednisolone in six patients. J Intern atrophy, microscopic colitis and pemphigoid change. Med 1991; 229: 443-6. JClin Gastroenterol 1989; 11: 216-9. 4 Lazenby AJ, Yardley JH, Giardiello FM, Jessurun J, Bayless 33 Wiener MD. Collagenous colitis and pulmonary fibrosis. TM. Lymphocytic ('microscopic') colitis: a comparative J Clin Gastroenterol 1986; 8: 677-80. histopathologic study with particular reference to collage- 34 Wang KK, Perrault J, Carpenter HA, Schroeder KW, nous colitis. Hum Pathol 1989; 20: 18-28. Tremaine WJ. Collagenous colitis: a clinicopathologic 5 Farah DA, Mills PR, Lee FD, McLay A, Russell RI. correlation. Mayo Ctin Proc 1987; 62: 665-71. Collagenous colitis: possible response to sulfasalazine and 35 Roubenoff R, Ratain J, Giardiello F, Hochberg MC, Bias local steroid therapy. Gastroenterology 1985; 88: 792-7. W, Lazenby AJ, et at. Collagenous colitis, enteropathic 6 Kingham JGC, Levison BA, Ball JA, Dawson AM. arthritis, and autoimmune diseases: results of a patient Microscopic colitis - a cause of chronic watery diarrhoea. survey. JR/seumatot 1989; 16: 1229-32. BMJ 1982; 285: 1601-4. 36 Flejou JP, Grimaud JA, Molas G, Baviera E, Potet F. 7 Teglbjaerg PS, Thayssen EH, Jensen HH. Development of Collagenous colitis: ultrastructural study and collagen collagenous colitis in sequential biopsy specimens. immunotyping of four cases. Arc/s Pat/sot Lab Med 1984; Gastroenterology 1984; 87: 703-9. 108: 977-82.