BRI EF COMMUN ICATION Occult celiac disease associated with lyrnphocytic sclerosing cholangitis I !UGI I J FREEMAN ML), WC PETER KWAN MD HJ FREEMAN , WCP KWAN. Occ ult celiac disease associated with lymphocytic scler osing cholangitis. Can J Gastroenterol 1994;8(4 ):249-252. A 60-year- old male wi th cle m1a ri tis herpctiformis a nd a previously trea ted lymphoma mvolving an inguinal lymph node developed abnormal li ver chem is tr y t es ts. Because of in termit te nt diarrh ea , additional studies revea led lymphocytic co litis and occult ce li ac disease lhat respondeJ co a gluten-free <li er. A liver biopsy done ro explore persiste ntl y abno rmal 1 i vcr chemistry rests showed a portal tract-cen- tred inflammatory process ch aracteri zed by biliary ductal proli fe ration, epithe lial lymphocytosis and concentric lameUar fibrosi s. Quanti rarion of immunoglobulins was normal and antimitochondrial antibodies were negative. Retrograde cho- langiograms showed radiological fea tures typica l of prima ry scleros ing cholangi- us. T he ep ithe lial lymphocycosis repor ted in gastric, sma ll and large intest inal mucosa of some patie nts with ccli ac disease may also be present in the biliary ducta l co lumnar ep ithelium. This report provides additional evidence that ce li ac disease may be a fa r more extensive pat hologi ca l process. Key Words: Celiac disease, EJ) ithe lial lymJ >h ocytosis, Gl uten-sensitive entero/>a th y, I nflammatory bowel disease, Liver di sease, LymJ>homa, Sclerosing ch ola ngitis Maladie coeliaque occulte associee a une cholangite sclerosante lymphocytaire RESUME : Un h omme de 60 ans atce int d' unc mal ad ie de Duhring Brocq et d'un lymphome inguinal ayant deja ere ~raitc, a co mmen ce a prese nter des resul rats d'enzymes hepatiques anormaux. A cause d\me d ia rrhce in termittcnte, d'autres cxamcns Ont Cte effec tUCS et Ont reve[e une co litc [ymphocytaire et une maladic coe liaque occul te qui o nt rcpondu a une alimc nca ri on sans gluten. Une biopsie hcparique effectuee pour deter miner la ca use de la persistan ce d es resultats d 'ana lyscs anor maux a demontre un processus infla mmato ire ce ntre au continued on next page Dcparnnenr uf Medicine (Gas[rc><'ntcrolo,!f.y), Urnversiiy Hospira/ and Universiry of Bnusit Ccilmnbia, V1mrn111'L'1., /Jriris/t Co/11mbia C1mcs/io11dence and re/mnts: Dr 1-/11gh Fn.'e111m1, ACU F-137, Universiry I los/iical (UBC me), 2211 \Xlesbrooh Mall, Vanco1wer, /Jri[is/1 Colrnnhia V6T lW/5. Tele/>hon<' (604) 822-7216 Rcceiwd for p11blicarion Ocrober 19, 1993. Acce/>tecl Jcmuciry 20, 1994 C/\N J 0/\STROENTEROI Vl)I 8 Nt) 4 JULY/AUGUST 1994 P REV IOUS REPORTS I JAVE DESCRIBED hepatobiliary tract ab norma li ties in ce liac disease, including chronic cholestatic syndromes ( l-3 ). In deed, the coexistence of celiac disease and primary bi li ary ci rrhosis is already well described in over 20 pat ients, including previous reporrs from rwo different Ca- nadian teaching hospitals (4,5). Per- haps less well appreciated arc the very rare reports of pri mary sclernsi ng chol- angitis associated with celiac disease (3,6) or lymphoma (7), a cond iti on a lso known to occur with increased fre- quency in patients with ccli ac d isease (8,9). Weight loss, malabsorption, bo ne disease, steatorrhea and elevated alkali ne phospht1rase activities may be seen as cnmmon fcmu res in both celiac d isease and either of these hepato- hiliary tract disorders so that at an early stage of the ir coexistence, diagnosis of one or the ocher conditinn may he missed. T he pmhological fea tures in the small intestine of ccliac disca~c arc well known. T hese include blunting of the sma ll intest inal mucosa! vi ll i, expan- si on of the lamina propria hy lympho- cytes and plasma cells, crypt hyper- p la sia and marked infiltration of the villnus epithelium by lymphocytes with accompanying epithelial cell vacuol i- :ation and flatteni ng ( IO). These in- 249
Transcript
BRIEF COMMUN ICATION
Occult celiac disease associated with lyrnphocytic
sclerosing cholangitis
I !UGI I J FREEMAN ML), WC PETER KWAN MD
HJ FREEMAN, WCP KWAN. Occult celiac disease associated with l ymphocytic sclerosing cholangitis. Can J Gastroenterol 1994;8(4 ):249-252. A 60-yearold male wi th clem1arit is herpctiformis and a previously treated lymphoma mvolving an inguinal lymph node developed abnormal liver chemistry tests. Because of intermittent diarrhea, add itional studies revealed lymphocytic colitis and occult celiac disease lhat respondeJ co a gluten-free <lier. A liver biopsy done ro explore persistently abnormal 1 ivcr chemistry rests showed a portal tract-centred inflammatory process characterized by biliary ductal proli feration, epithelia l lymphocytosis and concentric lameUar fibrosis. Q uanti rarion of immunoglobulins was normal and antimitocho ndrial antibodies were negative. Retrograde cholangiograms showed radio logical features typical of primary sclerosing cholangius. T he epithelia l lymphocycosis reported in gastric, small and large intestinal mucosa of some patients with ccliac disease may also be present in the bilia ry ductal columnar epithelium. This report provides add it ional evidence that celiac disease may be a far mo re extensive patho logical process.
Maladie coeliaque occulte associee a une cholangite sclerosante lymphocytaire
RESUME : Un homme de 60 ans a tceint d'unc maladie de Duhring Brocq e t d'un lymphome inguinal ayant deja ere ~raitc, a commence a presenter des resul rats d'enzymes hepatiques anormaux. A cause d\me diarrhce intermittcnte, d'autres cxamcns Ont Cte effectUCS et Ont reve[e une colitc [ymphocytaire et une maladic coeliaque occul te qui ont rcpondu a une alimcncarion sans gluten. U ne biopsie hcparique effectuee pour determiner la cause de la persistance des resultats d'analyscs anormaux a demontre un processus inflammatoire centre au
continued on next page
Dcparnnenr uf Medicine (Gas[rc><'ntcrolo,!f.y), Urnversiiy Hospira/ and Universiry of Bnusit Ccilmnbia, V1mrn111'L'1., /Jriris/t Co/11mbia
C1mcs/io11dence and re/mnts: Dr 1-/11gh Fn.'e111m1, ACU F-137, Universiry I los/iical (UBC me), 2211 \Xlesbrooh Mall, Vanco1wer, /Jri[is/1 Colrnnhia V6T lW/5. Tele/>hon<' (604) 822-7216
Rcceiwd for p11blicarion Ocrober 19, 1993. Acce/>tecl Jcmuciry 20, 1994
hepatobiliary tract abnormali ties in celiac disease, including ch ronic cholestatic syndromes ( l -3 ). Indeed, the coexistence of celiac disease and primary bi liary cirrhosis is already well described in over 20 pat ients, including previous reporrs from rwo different Canadian teach ing hospitals (4,5) . Perhaps less well appreciated arc the very
rare reports of pri mary sclernsi ng cholangit is associated with celiac disease (3,6) or lymphoma (7), a cond ition also known to occur with increased frequency in patients with ccl iac d isease (8,9). Weight loss, malabsorption, bone disease, steatorrhea and elevated alkali ne phospht1rase act ivities may be seen as cnmmon fcmu res in both celiac d isease and either of these hepatohiliary tract disorders so that at an early stage of their coexistence, diagnosis of one or the ocher conditinn may he missed.
T he pmhological features in the small intestine of ccliac disca~c arc well known. T hese include blunting of the small intestinal mucosa! vi ll i, expansion of the lamina propria hy lymphocytes and plasma cells, c rypt hyperplasia and marked infi ltration of the v illnus epithelium by lymphocytes with accompanying epithelial cell vacuoli:ation and flatteni ng ( IO). These in-
249
FREEMAN AND KWAN
niveau <lu sysccme porce et caraccerisc par une proliferation au nivcau des canaux biliaires, une lymphocycosc epichcliale et une fibrose lamella ire concencrique. Le dosage des immunoglobulines s'est revele normal et les anricorps anri-micochondrics negatifs. Les cholangiographies retrogrades one rcvcle des signes ra<liologiques typiques d'une cho langite sclerosante primaire. La lymphocytose epithclia le obscrvee Jans !es muqueuses de l'esromac, du petite intestin et Ju gros inrestin de certains patients atteincs de maladie coel iaque peur cgalement erre presence clans !'epithelium colummella ire des canaux biliaires. Cc rappon procure d'aucres preuves a l'effec quc la malaJie coeliaque peut ctre un processus pathologique heaucoup plus invasif.
nammatory changes have generally been described in the duodenum and jejunum ( 11) as well as ileum ( 12) of palienri. wirh ccliac disease. In addi tion, lymphocytosis involving the rectal surface epirhel ium in rarients with ccliac disease has been reported ( 13-15), as well as a distinc tive form of inflammatory change in gastric biopsies, previously described as lymphocyric gastri tis ( 16). Because of these observations in rmients with ccliac d isease, it has heen suggested that the histological lesions of epithelial lymphocytosis may have a wide degree of distribution within the gnstrnintestinal tracl ( 16 ). The present report describes a patient with dermatitis herpetiformis and lymphoma leading to a diagnosis of occult celiac disease, a previously well studied re lat ionship ( l 7, 18), alnng with an associated lymphocyric coliLis ( 15). In this patient, however, a rather unique constellmion of findings were a lso present including classical laboratory and raJiok>gical changes of primary sclerosing cholangiris assoc inred wiLh a portal tract cen tred primarily lymphocytic inllammatory process.
CASE PRESENTATION A 60-year old male was referred in
June 1992 for further evaluation of abnormal liver chemistry tests and diarrhea for at least tme year. In 1970, dermatitis herpetiformis was diagnoseJ; he was trcaled wilh inrermit lent clapsonc. In 1976, an enlmged right ingu inal lymph node was removed; a localized nodal lymphoma was detected and he was treated wirh chemotherapy and radiotherapy. No recurrent lymphoma was seen during follow-ur m the British Columhia C,mcer Agency in Vancouver. In May 1991, however, abnormal
scrum chemistry tesls were first seen: alkali ne phosphatase, 3 13 IU/L (normal 29 to 133); a lanine aminotransferase, 61 IU/L (normnl 7 to 35); and asparrare aminotransferase, 67 IU/L (normal 5 to 52). Because of diarrhea (nne to four semi formed or loose s tools per day), barium radiographs of the upper gastroin lestina l tracl were done in August 199 1. These were normal. A n abdominal ulrrasound wns also normal. Scrum chemistry tests were repeated in March 1992 (alkaline phosphmase, 417 lU/L; aspanate aminotransferase, 85 IU/L) and May l992 (alka line phosphatase 555 IU/L; asparcare aminoLransfcrase, 124 J U/L).
A t the palienr's initial review at University l lospiral in Vancouver, British Columbia , in June 1992, physica l examination was normal. There was no lymphadenoparhy and his liver and spleen were nor enlarged. There were no peripheral stigmata of chron ic liver disease. Laboratory investigations revealed : hemoglobin, 11 8 (normal 140 to 180 g/L); whi re blood cell count 4.4X I09 (normal 4.0 to l l.Oxt09
); and normal serum iron, iron binding capacity, ferr itin, carotene, folic acid and vitamin B12. A bo ne marrow aspirate showed iron bur no lymphoma. Upper gasLrninrestina l endoscopic evaluation in June 1992 was nmmal. There were no varices anJ the slomach anJ small in testine were macroscopically normal. Small bowel biopsies, however, showed a severe 'Oat' lesion with crypt hyrerplastic vi llous atrophy cha racreristic of celiac disease. Gastric biopsies were normal with no lymphncyric gastritis ( 16). Flexible sigmoi<loscopy was normal but a colonic biop~y showed features of epithelial lymphocytnsis ( 15). Scrum chcmisrry tests were more ab-
normal (a lka line phospharnsc, 630 lU/L; aspanate aminotransferase, 173 IU/L). Ant inuclear ,md amimimchondrial amihodie:. we re negative. lmmunoglobulin G, A and M quamitat ion was normal. Fecal cultures and parasite examinations were negative. Abdominal ulcrasmmd, ,1bdominal and pelvic compuled lomography scans were normal; lymphadenopathy was nm detected. Pcrcurnncous needle liver biopsy (Figures 1,2) revealed normal liver lobules with bile-Juel centred inflammawry change, especially with lymrhocytic infiltrates. The limiLing plates were incact and the re was nn lobular inOammmion. Focal damage to reactive hilc duct epithelium wilh hile ductular proliferation was present. Larger portal tracts showed inOammation with some fibrosis present in a conccmric lnmcllar mrangemem; severe reactive atypia of bile duct epilhclial cells wa, a lso present. Lymphoma was not pre~enr. Following liver biopsy, a glutenfree diet was initiated. By July 1992, his bowel hahil was normal with one formed sLOol daily. Scrum chcmislry lests had improved: a lkali ne phosphatase, 465 IU/L; and asparcatc aminotransferase, 168 IU/L. Endoscopic retrograde cholangiography (Figure 3), however, showed multiple stenoses within the imrahepalic bilia ry tree associated with areas of proximal dilatation. A long tubular fixed narrowing with irregular margins extended throughout Lhe length of the common bile Juel hut contrast was seen tn now into the duodenum. T he appearances suggested sclerosing cholangiris involving both the intrahcpatic and extrahepatic biliary tree. A duodenal hiops\' done at lhc rime nf the cholangiogram showed histological improvement with reappearance of villi . Afler int roduction of the gluten-free Jiet, serum chemistry rest:, in November l 992 (alkaline phosphatase, 287 lU/L; a:.parrnLe aminotransferase, 117 lU/L; a lanine aminotransferase, 93 IU/L) and March 1993 (a lkaline pho:,phacase, 224 IU/L; aspanare am inotransferase, 51 lU/L; alanine mninmransfcrase, 53 IU/L) were improved but not normal; an abdominal ullrnsound repeated inJanu,1ry 1993 was normal.
250 CAN J GA:i'TROENTEROL VOL 8 No 4 JULY/AUUUST l 994
~ .. Figure l) Lm!r bioJ>sy showing /)()rwl crac1 centred inflammator)' process mtli lym/)hucyws and concl'ntric lamellar filn·os is ( h.:mmoxylin and eosrn, x7{)
Figure 2) Liver hio(>;;)' showing liig/ier f>Ower view of /)orwl 1rnC1 from Figure I . Reac1ive biliary d11c1al celL~ are />resent wi1/i prcdominmel)' lymplwcytic infiltrate 111 the e/)it/iel111m. In perid11ccal zone, a more dense ccmcl'ntric lamellar fibrosis is J1resem (/iemawxylin and eosin, Xl47)
DISCUSSION The presented patient had histologi
ca ll y defined occult celiac disease tha t ll'Hs preceded by a long-standing history of dermatitis he rpeti formii, and a successfull y trea ted lymphoma, a relm ion ,h1p prev iously <lescribcd elsewhe re ( 17). Studies in this patient, however, also revealed the presence of lymphocytic colitis ( 15) an<l an antimitochondria l antibo<ly negative form of ch ronic chnlesta tic liver d isease. Further investigat ions showed a bile duct centred mllammacory process charac ter ized by fihrosis, a predominance of lymphocvtes in duct epithe lium and cho langiographic features typical of primary ~clcrosing cholangit is involving the intrahepatic and extrnhepatic bile ducts. A number of he pawbiliary tract d borJers have been recorded in celiac disease including cho lcstatic liver diseases such as prima ry biliary c irrhosis (4 ,5). Although a commo n immuno logical has is may be present , ex tensive studies to date h ave fa iled LO identi fy a common genetic predisposit io n or common immunological a lteration in ccliac disen~c a nd prima ry biliary ci rrh osis (5). Changes of primary sclcrosing cholangius have been only very rare ly rec1>rded in patients with celiac disease (3,6), and the precb e relat ion ship becwecn celiac disease and primary ,clcrosing cholangitis has never been systecmuically explored (1 9 ). Either small bowel biopsy studies of patients with pr i1m1ry sclc rosing cho la ngi tis or
Figure 3) Cholangiogram showing incrnhe/)(ltic and excrahc/)(ltic duccal changes cy/>ical of />1 imary sclerosing cholangitis
cho hmgiographic studies of patients with celiac d b ease are needed to define this poten tially in triguing rela tionship mo re precisely. As in celiac disease,
many patients with prima ry sd erosing cholangitis are asymptomatic. Indeed , as is well known in celiac disease, our patient had only limited symptoms despite histological detect ion of both sma ll and large intestinal disease as well a:. eventual ch olangiographic documen tation of raLl,e r extensive intrahe pat ic and cxcrahepnt ic radiological changes. These findings further emphasize that biliary tract epi the lial changes may be more frequent in celiac disease than is apprec iated.
Add itional stud ies arc needed to elucidate t he natural history of the bi liary tract abnormalit ies in ccliac d isease and possible biliary tract responses in these patients to a gluten-free d iet. A lthough at least two previous studies indicated that nbnormal liver chemist ry tests (ie, aspartatc aminotran fcrase, alan ine aminotransfe rase, alkaline phosphatase activities) in celiac <lisease patients wi th various forms of hepatobilia ry disease improve with gluten rescriction (2,3)- as was apparent in this prcsenr patient with sclerosing cholangitis - it is premature to suggest that these impro\'ed blood tests were indicat ive nf a convincing biliary tract re-
C-\N J GASTROENTER(1l. VOL 8 No 4 JULY/AUGU:-., 1994 251
FREEMAN AND KWAN
sponse co a gluten-free dice. The origin of alkaline phosphatase activities measured in the serum include the hepatobi lia ry tract as well as bone and the intest ine as possible sources; each of these may be altered in celiac disease after introduction of a glucen-free diet . In an earlier report from the Mayo C linic exploring this novel association with primary sclerosing cholangit is (6 ), improvement in the celi ac d isease, but nor the bilia ry cract disease, was recorded afte r introd uct io n of a gluten-free diet. U nfortunately, in that repo rt, two of the three recorded pacien ts with celiac d isease also apparently had concomitant chronic ulcerative colitis (ie, one with ' inact ive' quiescent colonic d isease and one with 'mild' or 'min imal change' colo nic disease), a cond ition also commonly associated with primary sclerosing cholangitis. Even extensive histological studies may not be able to
NO, Norden A, Scenstam M. Hepatic injury in aJult coeliac disease. Lancet I 977;ii:270-2.
3. Jacobsen MR, Fausa 0, Elgjo K, Schrumpf E. l lcpatic lesions in adult cocliac disease. Scand J Gascroenccrol I 990;25:656-62.
4. Ili ffe GD, Owen DA. An association between primary biliary cirrhosis and coeliac disease. Dig Oas Sci l 979;24:802-6.
5. Freeman l lJ. Cel iac d iscase associated with primary biliary cirrhusis in a Coast Salish native. Can J Gastroenterol 1994;8: l 05-7.
6. I lay JE, Wiesner RH, Shorter RG, LnRusso NF, Baldus WP. Primary sclcrosing chol,mgicis anJ ccl iac di~ease. A novel association. Ann Intern Med 1988; 109:7 13-7.
7. Alpert LI , Jindrak K. IJ ioparhic retroperitoneal fibrosis and sclerosmg choh111g1ti:. as,ociared with a reticulum cell sarcoma. Gastrocncerology 1972;62: 111-7.
8. l larris OD, Cooke WT, Thompson H, Waterhouse JAH. Malignancy 111 aJult cucl iac dbeasc and idiopachic steamrrhea. Am J Med I 967;42:899-912.
9. Logan RFA, Rilkind EA, Turner ID, Ferguson A. Mortalicy in celiac disease. Gastroencerolngy I 989;97:265-7 1.
252
address conclusively this issue. Previous pathological studies have emphasi:ed the predomi nately lymphocycic nature of the porta l inflammatory process in ccliac associated liver disease ( l ). Detailed quant itative scudies of intraepithclial lymphocyte numbers in treated ccliac d isease have shown a persistent e levation in the intestine despite a gluten-free d iet (20,21). Thus, the bi liary t rac t respo nse co a gluten-free diet might be di fficu lt to document if the defining pathological end-point consists of lymphocyte counts in ductal ep ithelium. Increased cl inical awareness of th is 'more than chance' ( 19) association of sclerosing cholangitis with celiac disease, however, may eventually permit a more detailed exploration of a possible biliary response co gluten restric tio n.
Previous studies have documented a wide array of immunological abnormalicies in celiac d isease m, well as scleros-
10. Dobbins WO. Small bowel biopsy in malabsorptave states. In: Norris I IT, eJ . Pathology of the Colon, Small Intestine and Anus. New York: Church ill Livingstone, 1986: 121-65.
11. Rubin CE, Brandborg LL, Phelps PC, Taylor H. Studies of celiac disease. Part l. The apparent identical and specific nature of the duodenal and proximal jejuna! lesion in ccliac disease and 1Jiopachic sprue. Gastroenterology L 960;38: 28-49.
12. Brow J, Parker F, Wemstein WM, Rubin CE. The small intestinal mucosa in dermat itis herpeciformas. Pan l. Severity and distribut ion of che small 1111 eslinal lesion and associmeJ malabsorption. Gastroenceroloi..ry 197 1 ;60:355-62.
13. Austin L, D-1bbins W. SrnJ ies of the rectal mucosa in ccliac sprue: the intraepithclial lymphocyte. Gut I 988;29:200-5.
14. Dobbms W, Rubin C. Studies of the rectal mucosa in ccliac sprue. Gastroenter,,logy l 964;47:471-9.
15. Wolber R, Owen 0, Freeman H. Colonic lymphocytosas 111 patients with celiac sprue. I !um Pacho! 1990;2 I: 1092-6.
16. Wolber R, Owen D, DelBuono L, Appelman I I, Freeman H. Lymphocytic gastritis in patients with celiac sprue or spruclike mtestinal J ise,1se. G:1stroenrcr<1logy 1990;98:3 I0-5.
ing cho langitis (22-24), and variou~ theories have been noted to explain the concomitant presence of celiac disease and hcpaLObilia ry trnct d isease. Possibly, immune complexes are formcJ wich a common antigenic basis resulting in t issue damage; no specific antigen, however, has been detected. Alte rnacively, diminished suppressor T cell functio n mighc permit effector cywcoxic lymphocytes LO alte r a modifying antigen, like glu ten. These effector cells might then recognize and attack a pac ienc's own histocompat ihil ity antigens, such ns human leukocyte ant igen B-8 and dcnxyribose- 3 phenotypes recognized in high incidence in hoth diseases ( 19), and possihly present in high concentrations in biliary and intest inal epithel ia l cells. More irnmuno logicnl studies arc needed to elucidate further chis intriguing relationship between ccliac disease and lymphocytic sclcrosing chol:mgitis.
abdominal lymphoma. Presenting mamfcstauon of eel iac sprue or complicming J ermatius herpetiform1,. Am J Med I 977;63:585-94.
18. Freeman HJ, Chiu BK. Mult ifoc::il ~mall bowel lymphoma and lmcnt cel iac sprue. Gastroencerology 1986;90: 1992-7.
19. Schrumpf E. Association of primary sclemsing cholangnis and ce laac disease: fac t or fancy? Hepatology J 989;6: I 020-1.
20. Ferguson A, Murray D. Qu:m1 itation of intraepithelial lymphocy1es in human JCJlmum. Gut 1971; 12:988-94.
2 I. Holmes GKT, Asquith P, Stokes PL. Cellular infilitrate of jejuna! biopsies in adult cocliac Jiscase in relation co gluten withdrawal. Gut 1974; 15:278-83.
22. McFarlane JG, WoJcicka BM, T sanwulas DC, Pnrun,mn BC, Eddleston AL, William, R. Leukocy1c migration inhibition m respomc co biliary antigens in primary bi liary cirrhosis, sclerosing cholangiris, and ocher chronic liver diseases. Gamoenterology 1979; 76: 13 33-40.
24. Minuk GY, Angus M, Brickmnn CM. Abnormal clearance of unmunc complexes from the circulaunn of patients with primary scleros111g cholangaus. Gastrocnterology 1985;88: 166-70.
CAN J GA'>'TROENTEROI VOL 8 No 4 JULY/ AUGUST 1994
