Mepicise Copyright © 1976 by The Williams & Wilkins Co. Vol. 55, No.4 Printed in USA THE EXTRA-INTESTINAL COMPLICATIONS OF CROHN’S DISEASE AND ULCERATIVE COLITIS: A STUDY OF 700 PATIENTS ADRIAN J. GREENSTEIN, M.B., B.CH.,, F.A.CS., F.R.C.S, (ENG, Ep.)* HENRY D. JANOWITZ, M.D., MSS., F.A.C.P.** ano DAVID B. SACHAR, M.D, RACP., RAC.G.** INTRODUCTION Although extra-intestinal complications of Crohn's disease and ulcerative colitis have been discussed in some detail by various authors, it seems useful to formulate a pathogenetic classi- fication and to determine the incidence in a large series of patients. The present study is devoted to a consideration of extra-intestinal complications in Crohn’s colitis and ileocolitis and to a comparison of their incidence with that in regional enteritis and ulcerative colitis. CLINICAL MATERIAL, ‘The data for this study were obtained from a review ‘of 700 patients with inflammatory bowel disease seen at the Mount Sinai Hospital during the decade 1964-1973. There were 213 patients with regional enteritis, 223 with ileocolitis, 62 with Crohn's colitis, and 202 with ulcerative colitis. We have included in this group 160 patients with Crohn's disease involving the colon whose clinical features, intestinal complica. tions, and reoperation rates have been previously reported in detail in several other papers (34-38). ‘The diagnosis of Crohn's (granulomatous) disease was based on the criteria elaborated in detail by Lockhart-Mummery and Morson (48), Lindner et al (41), Korelitz etal (45), and Cook and Dixon (12). The major features required for the diagnosis of Crohn's disease included radiological, pathological, or endo- scopic evidence of deep trapsverse fissure formation or fistulization; asymmetrical mucosal involvement; ag- gregated inflammatory pattern; transmural inflam. ation; confluent linear ulceration; discontinuous or segmental disease; right-sided involvement; rectal sparing; and noncaseating epithelioid granulomas of the submucosa, skin, or lymph nodes. All indetermi- nate cases, and patients in whom ischemic colitis, * Assistant Professor of Surgery, Department. of Surgery, Mount Sinai School of Medicine of the City University of New York. ** Clinical Professor of Medicine, Head, Division of Gastroenterology, Mount Sinai School of Medicine of the City University of New York. *** Assistant Professor of Medicine, Mount Sinai School of Medicine of the City University of New York From the Department of Surgery and the Division of Gastroenterology, The Department of Medicine of the Mount Sinai School of Medicine of the City University of New York. amebiasis, tuberculosis, and obscure malignancy could not be ruled out, were excluded from this series. ‘The diagnosis of Crohn’s colitis was made by clinical and radiological criteria in all 62 patients, confirmed at laparotomy in 34 patients and proven by histological criteria in 27. All 223 patients with ‘leocolitis had radiological diagnosis, with surgical or histologic confirmation in 154 and 113 respectively. Similarly all 213 patients with regional enteritis had x-ray diagnosis, confirmed by surgery or histology in 169 and 106 respectively. ‘The diagnosis of ulcerative colitis was made by clinical, endoscopic and radiologic criteria in all 202 patients. The surgical specimens of all 98 operated patients were confirmed histopathologically as ulcera- tive or mucosal colitis. ‘The extra-intestinal manifestations recorded in the study were obtained by a retrospective review of the charts of these 700 patients. These manifestations were subdivided into three groups, which appear to be of differing etiologies, pathogenesis, and prognosis. Group A, which includes skin, joint, eye, and mouth manifestations, are considered “colitis related.” Group B, related to small bowel pathophysiology, imeludes malabsorption, renal stones, gallstones, and non-ealeulous hydronephrosis. Group C includes a smaller group of patients with non-specific com- plications comprising osteoporosis, liver disease, pep- tic ulceration and amyloidosis. RESULTS ‘The results of this study are set forth in Table 1, The major finding is that the incidence of Group A inanifestations is higher (p < 0.001)* in patients with colonic disease (42%) than in those with involvement confined to the small bowel (23%). The occurrence of multiple mani. festations within this group is shown for 160 patients with (ileo) colitis in Venn diagram and histogram form in Figures 1 and 2. GROUP A. “COLITIS RELATED MANIFESTATIONS. (Table 1) Joint Manifestations ‘Those patients with arthritis were classified into the categories previously used by Wright and Watkinson (62) for ulcerative colitis: colitic = By chi-square test. 401402 GREENSTEIN, JANOWITZ AND SACHAR ASSOCIATIONS OF THE 4 MAJOR COLON-RELATED MANIFESTATIONS IN. 62 OF 160 PATIENTS WITH CROHN'S GOLITIS AND ILEOCOLITIS, a 62 cron NUMBER OF PATIENTS JOINT SSOCIATIONS OF THE 44 MAJOR COLON-RELATED MANIFESTATIONS IN ‘OF 160 PATIENTS WITH 'S COLInS AND ILEOCOLITIS, SKIN a vie viv] EYE Ey 7 | MouTH vv Fig. 2 (usually unilateral or monoarticular, in the large joints particularly in the lower limbs, generally with exacerbation of the disease), polyarthritic (multiple peripheral joints), spondylitic and combinations of groups. Poorly defined multiple and migrating peripheral ar- thralgias were included in the polyarthritic group. These types and their distributions are shown in Tables 2 and 3. Arthritis occurred in 164 of the 700 patients (23%). Ankylosing spondylitis was diagnosed by x-ray in 27 patients (4%), but since not all our patients were examined radiologically to ex. clude this diagnosis, the incidence may have been greater. On the whole, patients with co- lonic involvement manifested arthritis more frequently (27%) than those with only small bowel disease (14%). The occurrence of arthritis was the same (26%) in both ulcerative colitis and granulomatous ileocolitis, but it was signifi- cantly higher (39%) in Crohn’s disease limited to the colon (p < 0.05) Skin Manifestations The skin manifestations are enumerated in ‘Table 4. There were 108 of 700 patients (15%) with various skin diseases. Cutaneous complica- tions of Crohn’s disease confined to the small bowel (9%) were significantly less common (p < 0.05) than among any of the other patient groups (16-23%). The most frequently encountered lesion wasEXTRA-INTESTINAL COMPLICATIONS OF CROHN'S DISEASE AND ULCERATIVE COLITIS erythema nodosum, occurring in 15% of granulo- matous colitis, 8% of ileocolitis, 4% of regional enteritis, and 4% of the ulcerative colitis pa- tients. The incidence pattern of pyoderma gan- grenosum was different, being greater in the ulcerative colitis group (5%) than in the com- bined Crohn's colitis and ileocolitis group (1.4%). Thus erythema nodosum was signifi- cantly more frequent in Crohn's disease (p< 0.05), while pyoderma gangrenosum occurred more often in ulcerative colitis (p < 0.05) ‘These lesions usually responded to medical or 403 surgical treatment of the basic disease, and also improved during periods of remission. Ery- thema nodosum, for example, occurred as an episodic manifestation in many patients, with synchronous exacerbation and simultaneous resolution of both the skin lesions and the bowel disease. Some patients, however, were refrac: tory to treatment. In fact, one patient with granulomatous disease developed pyoderma- like lesions with purulent discharge while on therapy. In three patients with Crohn's colitis, skin TABLE 1 Extra-Intestinal Manifestations of 700 Patients with Inflammatory Bowel Disease Ulcerative Granulomatous Granulomatous Regi colitis eoltis Hleocolitis enteritis Total no. of patients in series 202 62 228 aa Group A: “Colitis” Related Joint 53 (26%) 24 (39%) 57 (26%) 30 (14%) Skin 39 (19%) 14 (28%) 36 (16%) 199%) Mouth 8(4%) 71%) 7 (3%) 63%) Eye 914%) (13%) 10(4%) 21%) TOTAL* 90 (45%) 32 (55%) 83 (37%) 50 (23%)** Group B: Related to patho- physiology of small bowel: Malabsorption 00%) 0(0%) 22. (10%) 23(11%) Gallstones 10(5%) 36%) 22.10%) 27 (13%) Renal stones 116%) 36%) 21 (9%) 18 (8%) Non-calculous hydronephrosis 00%) 2(3%) 14 (6%) 126%) Group C: Non-specific Osteoporosis 6(3%) 315%) 94%) 5 (2%) Liver 15 (7%) 4(6) 10(4%) 4(2%) Peptic ulcer 15 (7%) 4(6%) 26 (12%) 23(11%) Amyloidosis 0(0%) 12%) 3 (1%) 1(0.5%) * Many patients with multiple manifestations **UC > RE (X? = 20: P < 0.001) GC > RE (X* = 18: P< 0.001) GIC > RE (X* ~ 10: P < 0.05) GC > GIC (X? = 4.1: P< 0.05) UC > GIC (X? = 2.36: NS) GC > UC (NS) TABLE 2 Classification of Arthritie Manifestations in 164 of 700 Patients with Inflammatory Bowel Disease ~ Ulcerative Granulomatous Granulomatous Regional colitis colitis eocoltis enteritis Total no. of patients ins 202 62 223 213 ‘Colitic” arthritis 18 (9%) 117%) 24 (11%) 116%) Polyarthritis 27 (13%) 905%) 24 (10%) 136%) Spondylitis 1 2 3 3 “Colitis” + Spondylitis 1 1 6 2 Polyarthritis + spondylitis 0 1 1 Total 3 (26%) 24 (39%) 87 (26%) 80 (14%)* *UC > RE.X'=957P <0.05 GC >RE.X*-1845P 0.001 GIC > RE.X* - 8.98P < 0.005404 GREENSTEIN, JANOWITZ AND SACHAR TABLE 3 Distribution of Major Arthritic Manifestations in 164 of 700 Patients with Inflammatory Bowel Disease Ulcerative Granulomatous Granulomatous Regional colitis oltis ieocolitis ententis ‘Total no. of patients in series 202 62 223 213 ‘Total no. of patients with arthritis* 53 (26%) 24 (39%) 57 (26%) 30 (14%) Polyarthralgias 2 9 mw 13 ‘Temporo-mandibular joint 0 0 3 1 Spine: Cervical 0 ° 3 0 ‘Thoraco-lumbar 8 4 6 7 Arm: Shoulder 5 1 2 Elbow 2 4 Hand** 5 3 Leg Hip 1 1 6 3 Knee 9 5 4 8 Ankle 4 5 9 3 Foot 1 1 2 0 *G.C.> REX? 001 GC. > GLC. X* LP < 0.05 8.12P < 0.001 UC. >RE.X*=10.99P <0.001 GLC. > R.E.X*~8.98P < ** Hand and wrist frequently involved in polyarthralgias TABLE 4 ‘Skin Manifestations in 108 of 700 Patients with Inflammatory Bowel Disease “se Oh meee Total no. of patients in series 202 62 223 213 No. of patients with skin diseases 39 (19%) 14 (23%) 36 (16%) 19(9%)* Erythema nodosum 94%) 916%)" 178%) 84%) Pyoderma gangrenosum 106%)*** 1(1.6%) 31.3%) 20%) Dermatitis 7 1 6 6 Erythematous rash 4 1 2 0 Proriasis 2 ° 4 2 Stevens-Johnson syndrome 1 ° 0 Hyperkeratosis ° 1 1 0 Carcinoma 1 ° 2 ° Herpes zoster o ° 1 1 Urticaria 1 ° ° 0 Pityriasis 1 0 ° ° Lupus erythematosus 1 ° ° ° tiligo 1 ° ° ° Ecchymosis 2 0 ° ° *UC. > RE. X?=9.27P < 0.005 G.C.> RE.X?=848P <0.005 GLC. >RE.X* = 515P < 0.05 *G.C. > UG. X! = T5P < 0.05 “ULC. > GC. + GLC. X? = 5.5 P < 0.05 disease constituted a major problem. One pa- tient developed exfoliative dermatitis of the left thigh. Another manifested Stevens-Johnson syndrome involving skin, eye, and mouth. The third patient developed widespread erythema nodosum, first of the legs and later of the arms and shoulders. Maculopapular lesions devel- oped on the face, and the vesicles of aphthousEXTRA-INTESTINAL COMPLICATIONS OF CROHN’S DISEASE AND ULCERATIVE COLITIS stomatitis formed on the soft palate. The le- sions, confluent and purulent, ultimately re- sembled pyoderma gangrenosum. Aphthous Stomatitis Aphthous stomatitis was the mouth lesion most often seen in these patients. The clinical picture was one of ulcers on the floor of mouth, gums, upper and lower lip, palate, and uvula. ‘The lesions consisted of vesicles and areas of frank ulceration of an herpetic type, and they were often associated with vesicles and ery- thema nodosum of the skin. Two patients with ulceration of an herpetic type had similar rectal ulcers. We did not observe any granulomatous lesions of the gums or mouth. ‘The occurrence of stomatitis was relatively rare in the overall series (4%), but it was most frequent in granulomatous colitis (11%) (Table 1). The lesion either preceded or followed the onset of intestinal disease, and it was commonly found in association with other extra-intestinal manifestations such as skin and joint lesions (Fig. 0). Eye Manifestations Although a systematic ophthalmologic study of all 700 patients in this study was not done, 29 of 700 patients (4%) were noted to have some form of eye disease (Table 1). These disorders included conjunctivitis, recurrent episcleritis, and uveitis, Orbital myositis in one patient resulted in diplopia, and obliteration of a retinal artery in another caused a temporal field defect. As with the joint, skin, and mouth manifesta- tions, the incidence of eye complications was greatest in granulomatous colitis (13%) and least in regional enteritis (1%). GROUP 8, SMALL BOWEL RELATED MANU (Table 1) Malabsorption Except for those cases included in a research. series (29), absorption studies were done only in those patients suspected clinically of having malabsorption. The diagnosis of malabsorption was based on any one of the following three criteria: fat malabsorption was considered to be present if the stool fat averaged more than 6 grams per day in a 72 hour collection; earbohy- drate malabsorption was considered present if urinary p-xylose excretion in patients with normal renal function was less than 5 grams 405 after a 25 gram oral loading dose; vitamin Biz absorption was considered abnormal if less than 6% of radioactive vitamin Biz administered (Schilling test) was excreted in the urine over 24 hours. Malabsorption was clearly associated with small bowel disease. Forty-six of these 700 patients (6.7%) had unequivocal evidence of malabsorption, These cases were evenly distrib- uted between ileocolitis (22 patients, 20 of whom had undergone surgery), and regional enteritis (23 patients, 16 of whom had been operated upon). No patients with Crohn's coli- tis or ulcerative colitis had malabsorption. Ex- pressed in other terms, malabsorption was found in 10% of patients with involvement of the small bowel but in no patient with disease confined exclusively to the colon. Gallstones Gallstones were diagnosed either by flat plate of the abdomen, oral cholecystography, or lapa- rotomy. Although no systematic search was made for gallstones, 62 of the 700 patients were found to have them (8.9%). The incidence was highest in regional enteritis (13%), intermediate in ileocolitis (10%), and least in both ulcerative and granulomatous colitis (5%). The incidence among patients with small bowel disease was therefore significantly greater than that among patients with disease restricted to the colon (p < 0.05). Fifty-six per cent of the patients with gallstones had undergone no previous surgery. Genitourinary Manifestations Genitourinary manifestations, which in- cluded kidney stones, hydronephrosis and hy- droureter, ileovesical fistulae, and amyloid ne- phrosis occurred in 117 of 700 patients (17%) All but amyloidosis appeared to be related to specific intestinal pathophysiology. Kidney Stones Kidney stones, confirmed by intravenous py- clography, were found in 53 subjects (7.6%), with a slight preponderance in the small bowel groups, 8-9%, vs 5% in the colitis group. In 10 of these cases, stones were recognized as the cause of hydroureter or hydronephrosis. We have not obtained data on the composition of the stones, but the vast majority were radiopaque. In the patients with Crohn's disease, the stones were generally associated with major406 RI disease in the ileum, and usually with opera- tion, OF the 24 kidney stone patients with Crohn’s colitis and ileocolitis, 20 had undergone surgery (83%). Procedures included small bowel resection or reresection in nine; ileostomy plus either subtotal colectomy, proctocolectomy, or small bowel resection in seven; ileostomy alone in two; and bypass of the terminal ileum in two, Among the 18 regional enteritis patients with kidney stones, 16 had undergone surgery (89%): 13 with small bowel resection or reresection, 2 with bypass, and 1 with ileostomy. By contrast, only 4 of the 11 stone patients with ulcerative colitis (36%) had been subjected to colectomy and ileostomy. Non-Caleulous Hydronephrosis, and Hydroureter Non-ealculous hydronephrosis and hydrou- reter, demonstrated by intravenous pyelogra- phy, were found only in Crohn's disease pa- tients, comprising 26 of 436 patients (6%) with small bowel disease, and 2 of 62 patients (3%) with disease restricted to the colon. Hydrone- phrosis was usually unilateral (right-sided in all but two cases) and it resulted from extramural compression of the ureter by inflammatory mass, fibrous tissue, or abscess. Enterovesical Fistulae Enterovesical fistulae were documented by pneumaturia or fecaluria, and/or were proven radiologically. Fistulae occurred in 31 patient of whom 30 had small bowel disease. ‘Th represents an incidence of 7% among the 436 patients with ileitis or ileocolitis. Most of these patients presented with pneumaturia and recur- rent urinary tract infections, The development of enterovesical fistulae was an important pi mary or contributing reason for surgical resec- tion of the diseased segment, usually ileum, in this series GROUP c, NONSPECIFIC COMPLICATIONS (Table 1) Osteoporosis Osteoporosis or osteomalacia was found in 6 patients with ulcerative colitis (3%), 3 patients with granulomatous colitis (5%), and 14 pa- tients with disease localized to the small bowel (8%). Generalized demineralization was found in two patients. Other features were bone pains and pathological fractures of the vertebrae, ‘STEIN, JANOWITZ AND SACHAR femur, ribs, or tarsal bones. Three patients developed fractures while on steroid therapy. In another, osteoporosis appeared before the diag- nosis of colit Liver Disease Patients in this series were listed as having liver involvement if they had unequivocal evi- dence of either cirrhosis, hepatitis or liver ab- scess. The diagnosis of cirrhosis was established in every case by liver biopsy. ‘The diagnosis of hepatitis was based on the combined presence of frank jaundice and elevations of at least two out of three enzyme levels (alkaline phospha- tase, SGOT, SGPT) to at least three times upper limits of normal. ‘The diagnosis of liver abscess was confirmed at surgery. One addi- tional unclassified case was included on ac- count of massive hepatomegaly and a very high alkaline phosphatase level without jaundice or elevated transaminases. Liver disease occurred in a total of 33 patients (Table 1) comprising 15 with ulcerative colitis (7% of 202), 4 with Crohn's colitis (6% of 62), 10 with ileocolitis (4% of 223), and 4 with regional enteritis (2% of 213). Cirrhosis was found in seven patients: five with ulcerative colitis and one each with Crohn's colitis and ileocolitis. Hepatitis o curred in 24 cases: 10 with ulcerative colitis with Crohn’s colitis, 7 with ileocolitis, and 4 with regional enteritis. Most of these cases of hepatitis followed surgery or blood transfusion. No case of Azulfidine hepatic toxicity was noted in this group. One patient with ileocolitis and malabsorption presented with a markedly en- larged liver and elevated alkaline phosphatase which subsided spontaneously. One patient with ileocolitis developed a liver abscess. Peptic Ulceration Peptic ulceration was found in 68 of 700 patients (9.7%). The incidence was greater in the small bowel group, 49 of 436 (11%), than in the colon group, 19 of 264 (7%), but the differ- ence is not quite statistically significant (p > 0.05). Amyloidosis Amyloidosis occurred only in patients with Crohn's disease, with an incidence of 1%: 5 of 498 patients, one each with colitis and ileitis, and three with ileocolitis. All five patients hadEXTRA-INTESTINAL COMPLICATIONS OF CROHN’S DISEASE AND ULCERATIVE COLITIS renal involvement; in one, amyloid nephrosis contributed significantly to the patient’s death. DISCUSSION ‘The separation of extra-intestinal manifesta- tions of inflammatory bowel disease into the two main groups which we have proposed seems reasonably consistent with the data and with current ways of thinking about these disorders One group (“B") is clearly related to dis- turbed small bowel function: malabsorption of fat, carbohydrates, and vitamin Bis, clearly representing loss of small bowel absorption function especially in the ileum; gallstones, secondary to diminished ileal reabsorption of bile salts; kidney stones, due to fluid and electrolyte losses plus the recently described increased absorption of oxalate; ureteral ob- struction and enterovesical fistulae, secondary to direct extension of ileal disease. This group of disorders therefore occurs most often in pa- tients with Crohn's disease involving the ileum. The other group (“A”) appears to be more closely correlated to the inflammatory activity of the underlying bowel disease and to be associated with the involvement of the colon more than of the small bowel. In most cases, the incidence in Crohn's colitis was somewhat higher than in ulcerative colitis or ileocolitis, while occurrence in pure regional enteritis was relatively less common. By analogy with the arthritis of viral hepatitis, and in keeping with some evidence regarding circulating antigen- antibody complexes, these extra-intestinal manifestations may have an immunologic basis, possibly by the deposition of antigen-antibody complexes in synoviunt, skin, and choroid appa- ratus of the eye. Arthritis We subdivided our patients into those with predominantly monoarticular large joint (‘‘co- litie”) arthritis, those with polyarthritis, and those with spondylitis, as suggested by Wright and Watkinson (62). In all categories, the pa- tients with colonic disease had a higher inci- dence of arthritis than those with disease local- ized in the small bowel ‘The relationship between arthritis and ulcer- ative colitis has been frequently attested to since the original report by Bargen in 1930 (2) ‘There are considerable variations in the esti- mates of the frequency of this complication, 407 ranging between 4% and 22%. Wright and Watkinson (62), in a study of 269 patients with ulcerative colitis, found 45% with some form of arthritic manifestation. The distribution ac- cording to type of arthritis was similar in their series and in ours. They found the “colitic” type (monoarticular, asymmetrical, most frequent in lower limbs) among 11% of their ulcerative colitis patients, and we observed “colitie” ar- thritis among 9% of ours. Likewise, Wright and Watkinson noted ankylosing spondylitis in 6% of their series, while we found this complication in 4% of our own, ‘The association between Crohn's disease and arthritis found by other authors is substantiated by this report. The incidence of 14% in our 213 patients with disease localized to the small bowel is, however, considerably greater than the 4.5% in 600 cases reported by Van Patter (57), and the 3.14% in 542 cases reported from this institution by Crohn and Yarnis in 1958 (17). ‘The highest incidence among patients with Crohn’s disease occurred in those with purely colonic involvement (39%), and was comparable to the incidence in ulcerative colitis (26%). Skin Manifestations As with the other colitis associated manifes- tations, the incidence of skin lesions was highest in patients with involvement of the colon, and lowest in ileal disease. The 19% incidence in our patients with ulcerative colitis is within the 10-20% incidence range reported in other series (24, 51, 59). The occurrence of pyoderma gan- grenosum among 5% of our patients with ulcera- tive colitis is only slightly higher than the 3% frequency reported by Goligher (33), and signifi cantly greater than the 1.2% we found in Crohn's disease. Cutaneous involvement in Crohn's disease was well reviewed by McCallum and Kinmont (60), who noted an overall incidence of 44% in 138 patients, as contrasted with 14% of our 498 patients, but these authors included perianal disease in their review. Van Patter (57) could find only 5 cases of erythema nodosum and one of pyoderma gangrenosum among 600 cases of regional enteritis (1%), and Crohn and Yarnis (17) found erythema nodosum only 7 times in 542 patients with the disease (1.3%). While we saw pyoderma gangrenosum only rarely in Crohn's disease (1.2%), we noted erythema nodosum more frequently (6.8%) (Table 4).408 Mouth Lesions Our observed 4% incidence of mouth lesions is not much different from the 6% noted in a similar retrospective study of Crohn’s disease by Croft and Wilkinson (16). The reported incidence in a recent prospective study by Basu et al (3) was 9% for Crohn's disease and 2% for ulcerative colitis. Our patients did not have biopsies to charac- terize their oral lesions histologically, but both aphthous stomatitis as well as frank granuloma- tous invasion of the buccal mucosa have been recognized in Crohn's disease (5, 21, 26, 43). As with perianal lesions, the oral manifestations may precede, coincide with, or follow the onset of the intestinal phase of the disease. Eye Manifestations Cornell in 1955 (15) doubted the occurrence of any form of eye manifestation in Crohn’s dis- ease. The paucity of cases in the large series of Van Patter et al (57) and of Crohn and Yarnis (17) seemed to confirm this impression. Never- theless, there is a definite increase in the incidence of uveitis and other eye conditions in Crohn's disease, compared with the general population. The eye manifestations of Crohn’s disease include recurrent attacks of conjunctivi- tis, keratitis, and uveitis. The uveitis may be difficult to recognize and diagnosis may require slit lamp examination. Truelove (56), and Kore- litz and Coles (44), have found an excess of uveitis in Crohn's disease, as did Wright et al (62) and Edwards and Truelove (24) in ulcera- tive colitis, Crohn and Yarnis (17) mention iridocyelitis, keratitis, corneal ulceration, and phlyctenular conjunctivitis as focal manifesta- tions of Crohn's disease, but do not give any incidence figures. Nugent et al (61) found iritis in 4 of 59 patients (6.8%) with ulcerative colitis and 2 of 44 patients (4.5%) with Crohn's colitis. In our larger series, there was an incidence of eye manifestations of 4% in uleerative colitis, and 4% in ileocolitis, 1% in regional enteritis, but 13% (8 of 62) in granulomatous colitis. GROUP. B. MANIFESTATIONS RELATED TO SMALL. BOWEL PATHOPHYSIOLOGY Malabsorption Malabsorption was found in 9% of our pa- tients with Crohn's disease. The association with small bowel disease was so specific that the GREENSTEIN, JANOWITZ AND SACHAR presence of malabsorption could be used to localize the disease process. In colonic disease, malabsorption should alert one to probable small bowel involvement. In our series, the incidence patterns of malab- sorption substantiate the classical findings of Cooke and Brooke (14), and of Booth (7), that there is an only minimal occurrence of malab- sorption in ulcerative or Crohn's colitis, but a substantial frequency (10%) in ileocolitis and regional enteritis. These findings are in accord with those of Gerson et al (30) at this hospital. In a study of 44 patients with regional enteritis and 21 with granulomatous colitis, many of them represented also in our present series, these authors found that fat and vitamin Bis malabsorption were correlated with the length of ileal dysfunction, particularly resection, and occurred in all patients in whom the length of dysfunction exceeded 90 cm. Jejunal absorp- tive function as represented by the D-xylose test was preserved in most patients. Patients with inflammatory bowel disease localized in the colon showed no significant abnormality of absorption Gallstones ‘The incidence of gallstones in our series was clearly greater in patients with involvement of the ileum by Crohn’s disease. Of 213 patients with regional enteritis, 27 (13%) had gallstones, an incidence substantially less than the 31-34% reported by Cohen et al (11) and by Heaton and Read (40). The incidence of gallstones, al- though overlooked in earlier series, has been shown to be especially increased above normal in patients who have had ileal resection. The incidence of 5% in our patients with ulcerative and granulomatous colitis may reflect the fre- quency in the general population. ‘The pathogenesis of small bowel related gall- stones has been clarified in recent years. (1, 20, 41, 58). Disease or resection of the termi- nal ileum results in diminished bile salt absorp- tion with consequent cholertheic diarrhea and excessive bile salt losses. If the loss is large and continued, the synthetic capacity of the liver is unable to compensate for the bile salt depletion, and chenodeoxycholic acid and total bile acid pools fall progressively. The resultant redue- tions in hepatic bile salt secretion and in gall bladder bile salt/cholesterol ratio predispose to the precipitation of cholesterol and hence to gallstone formation.EXTRA-INTESTINAL COMPLICATIONS OF CROHN’S DISEASE AND ULCERATIVE COLITIS Genitourinary Complications The genitourinary complications of Crohn's ileitis and colitis have been well described by previous authors. They include nephrolithiasis (4, 17, 18, 19, 49), non-calculous hydronephrosis, and hydroureter (25, 31, 32, 42, 53), amyloidosis (60), ileovesical and ileoureteral fistulae , 46, 52), and urinary infection, All of these complications have been found in the present series of patients and they affect a considerable proportion (17%) of patients with inflammatory bowel disease. Non-calculous hydronephrosis and hydrou- reter in inflammatory bowel disease were first described more than 30 years ago by Hyams et al (42), and later by Ginzburg et al (31), Goldman et al (32), Present et al (53), and Enker and Block (25). These complications are caused by entrapment of the ureter in a retro- peritoneal inflammatory process on the surface of the psoas muscle, within the psoas fascia. This fascia may be breached by posterior fistuli- zation from the terminal ileum or colon. Renal calculi have been noted in ulcerative colitis (4, 18, 29, 49), regional enteritis (17, 19, 29), and granulomatous ileocolitis (29), and have been particularly prominent in patients with ileostomy (4, 29). Among 1100 patients with chronic inflammatory bowel disease, Grossman and Nugent (39) noted an overall incidence of urolithiasis of 3.2%, but the frequency was more than twice as high among those patients who had undergone surgery than among those who had not. Gelzayd et al (29) found an increased incidence of renal stone formation in granulo- matous disease (10%), with about equal fre- quency in ileocolitis (9%), and regional enteritis, (11%). Our incidence figures are similar to these findings. ‘The association of renal stones with ileostomy is of interest, and probably results from the reduced urine volume and sodium concentra- tion as has been demonstrated in these patients by Singer et al (54). In addition, periods of bed rest related to major abdominal surgery, epi- sodes of dehydration resulting from diarrhea, and increased oxalate absorption and hyperox- aluria related to ileal resection (9, 55), may all contribute to the association of renal stones with disease of the distal small bowel. Urie acid lithiasis has also been recognized as a complica- tion of ulcerative colitis, especially after ileos- tomy, with intestinal loss of alkali and excessive 409 urinary acidification contributing to the prob- lem (8, 29). In this series, we have not given consideration to the composition of the stones. ‘Thirty-one patients in this series developed a suspected or proven ileovesical fistula with pneumaturia and urinary tract infection. Pneu- maturia may be the presenting sign of regional enteritis (52), as occurred in one patient in this series. Ileovesical or colovesical fistulae from the sigmoid colon may occur in Crohn's ileitis, and colitis. Ileo-ureteral fistula, a rare finding, has also been described in this disease (6), but did not occur in this series GROUP C, NON-SPECIFIC COMPLICATIONS Osteoporosis and Osteomalacia The occurrence of osteoporosis and os- teomalacia in 3% of patients with small bowel involvement in this series is similar to the 5% in the series of Cooke (13), who confirmed the diagnosis by iliac crest bone biopsies in patients with bone pain and elevated serum alkaline phosphatase levels. The 3% incidence in ulcera- tive colitis is marginally greater than the 1.4% in the series of Edwards and Truelove (24). It is understandable that osteomalacia could result from impaired vitamin D absorption secondary to steatorrhea and defective micellar formation, but the reasons for its association with colonic disease are not clear, We have not examined the relationship of these complications to steroid therapy, nor have we directed any attention in this study to the fascinating problem of growth retardation in youngsters. Liver Manifestations Since a routine liver biopsy was not done in every one of our patients (and indeed would not have been clinically indicated or warranted), we would not over-stress the significance of our findings, but they do represent the clinical findings in a large series of patients with inflam- matory bowel disease. Our 4.7% overall inci- dence of liver disease is very similar to the 4.8% incidence observed by Edwards and Truelove in their large series of patients with ulcerative colitis (24). Yet in a careful microscopic study of the liver at the time of colectomy for ulcerative colitis, Eade and Brooke (23) found histological abnormalities in 90%, including inflammatory changes in 20% and cirrhosis in 3%. In a separate study, the same authors also showed hepatic abnormalities in 90% of 20 patients with410 Crohn's colitis (22). In these patients, the ma- jority (70%) had universal disease, and the remainder had extensive colitis with only rectal sparing. Two patients (10%) had micronodular cirrhosis. These authors found hepatic fatty infiltration and inflammatory changes in both ulcerative colitis and extensive Crohn’s colitis, but not in Crohn's disease involving predomi: nantly the small bowel. Clearly these high incidence figures for liver disease in Eade's series are a reflection of the thoroughness with which this complication was sought. Because of our strict criteria for diagnosis of liver disease, our figures are a conservative estimate of the total number of patients with liver involvement, ‘Nonetheless, our findings seem to bear out the impression that liver disease, apart from cirrho: sis in ulcerative colitis, is from the practical standpoint rarely a serious complicating feature of inflammatory bowel disease. Peptic Ulceration Peptic ulceration was found in 6% of 62 patients with Crohn’s colitis, 12% of 223 pa- tients with ileocolitis, and 11% of 213 patients with regional enteritis. ‘The latter figure is slightly greater than the 8% incidence observed by Fielding and Cooke (27), and similar to the autopsy incidence of 12% reported by Chapin et al (10). Although we found peptic disease more frequently in patients with small bowel disease than in patients with disease limited to the colon, it is difficult to assess the significance of any of these incidence figures in view of the uncertainties regarding the incidence of peptic ulceration in the general and hospital popula- tions, and also in view of the unknown contribu- tions to the problem from medications, includ- ing steroids and salicylates. Amyloidosis Five patients in this series developed amyloid disease. Werther and co-authors (60) have de- seribed five other ileitis patients from the Mount Sinai Hospital who had amyloidosis discovered at postmortem examination, but all five of our patients had developed renal involve- ment with nephrotic syndromes during life; in one, advanced renal damage was a significant factor in his death. Chronic inflammation, occasionally chronic suppuration, plasma cell proliferation (occa- sionally seén in sheets in the involved area of GREENSTEIN, JANOWITZ, AND SACHAR Crohn's disease), and possibly steroid therapy may be involved in the pathogenesis of this complication. There is some scanty evidence that resection of the granulomatous disease may lead to regression of hepatic and renal amyloid (28). SUMMARY The records of a series of 700 patients with inflammatory bowel disease, 498 with Crohn's disease and 202 with ulcerative colitis, have been analyzed to determine the relative inci- dence and characteristic features of their extra- intestinal manifestations. The group with Crohn's disease included 62 with colitis, 228 with ileocolitis, and 213 with regional enteritis. ‘A consideration of the clinical patterns and an understanding of their pathophysiology sug- gested a subdivision into two main groups: one “colitis related” and one related to the patho- physiology of the small bowel. There was also a small nonspecific third group. Group A, colitis related, comprises j mouth, and eye disease. The complications might be immunologically determined, were closely associated with active inflammation, and often responded to medical or surgical treatment of the underlying bowel disease. They occurred in 36% of the entire series of patients: joints were involved in 23%, skin in 15%, and mouth and eye each in 4%. Pyoderma gan. grenosum was observed most often in ulcerative colitis and erythema nodosum most often in granulomatous colitis. The incidence of Group A complications was higher in disease involving the colon (42%) than in disease restricted exclu sively to the small bowel (23%). There were interrelationships among the various members of Group A, with multiple manifestations occur- ring in a third of affected patients. Group B, related to small bowel Pathophysiology, includes malabsorption, gall- stones, kidney stones, and non-calculous hy- dronephrosis and hydroureter. Disorders in this group were generally related to the severity of the disease in the small bowel and tended to persist even in the absence of active inflamma- tion. In contrast to Group A, this group oc- curred most frequently in small bowel disease, and least in colonic disease. Malabsorption was virtually confined to the patients with small bowel disease (10% incidence), while gallstones and renal stones were also both more frequentEXTRA-INTESTINAL COMPLICATIONS OF CROHN’S DISEASE AND ULCERATIVE COLITIS. in Crohn’s disease (11% and 9% respectively), the latter usually in association with small bowel resection or ileostomy. Group C, found in a small percentage of patients, consists of nonspecific complications, including osteoporosis (3%), liver disease (5%), peptic ulcer (10%), and amyloidosis (1%). BIBLIOGRAPHY 1. Admirand, W. J. and Small, D. M.: The physico- chemical basis of cholesterol gallstone forma- tion in man. J. Clin. Invest, 47: 1048, 1968, 2. Bargen, J. A. and Weber, H, M.: Regional migra- tory chronic ulcerative colitis. Surg. Gynecol. Obstet., 50: 964, 1930 3. Basu, M.'K., Asquith, P., Thompson, R.A. and Cooke, W. T.: Oral manifestations’ of Crohn’s disease. Gut, 16(4): 249-254, 1976. 4. Bennett, RC. and Hughes, 'E. 8. 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