To investigate factors which predispose to relapse in patients with ulcerative colitis, we conducted a survey to compare the events occurring in the four weeks preceding the clinic attendance of 62 outpatients in remission with those taking place in the same period before the onset of relapse in 21 patients attending with active disease. The only event which occurred significantly more often in patients who subsequently relapsed was ingestion of paracetamol and other inhibitors of prostaglandin synthesis (76% (16/21) relapse vs 39% (24/62) remission, p less than 0 . 01). Recent upper respiratory tract infection (38% vs 26%) was not significantly more common in patients in relapse than in remission, and emotional stress, atopic events, antibiotic treatment, dietary indiscretions, foreign travel, and gastroenteritis were relatively rare in both groups. The surprisingly high prevalence of analgesic ingestion before relapse itself requires confirmation but does lend indirect support to the theory that colonic mucosal prostaglandin deficiency induces relapse in some patients with ulcerative colitis.
A group of 18 patients with stable ulcerative colitis involving the entire colon for at least eight years was subjected to a biopsy of normal appearing rectal mucosa and followed prospectively over four years for the development of either dysplasia or cancer. Goblet cell glycoconjugate structure was examined in the rectal biopsies using fluorescein conjugated lectins. At the beginning of the study, 13 of the 18 patients had abnormalities of goblet cell mucin or cytoplasmic glycoconjugates in the rectal biopsies. Dysplasia subsequently developed in six and carcinoma in one of these patients. Among the five patients with normal lectin binding studies in the initial rectal biopsies, colonic dysplasia has subsequently developed in one. The abnormalities seen in the rectal goblet cells resembled in part those previously seen in immature and neoplastic colonic cells. The dysplastic tissues all contained the form of mucin which has been found in other neoplastic colonic tissues. This preliminary report after four years of prospective study suggests that abnormalities of glycoconjugate structure may be associated with, and may precede, neoplastic events in the setting of chronic ulcerative colitis.
5-aminosalicylic acid (5-ASA) is a new treatment for patients suffering from ulcerative colitis but only limited information is available about its rectal absorption. We therefore studied seven patients with ulcerative colitis in remission, and five with active disease to determine acetylated and free 5-ASA plasma concentrations and urinary acetyl 5-ASA after the administration of three different types of enemas: (2 g 5-ASA/100 ml, 4 g/100 ml, and 200 ml). In patients in remission urinary acetyl 5-ASA excretion was dose and volume dependent (p less than 0.01; p less than 0.05) but this correlation was absent in active disease. Because aminosalicylates are usually eliminated through the kidney, these low values (10% in active disease and 19% in those in remission) suggest that the beneficial action may be local. Urinary recovery was significantly lower in patients with active disease (p less than 0.01; p less than 0.02). No accumulation of 5-ASA was found in plasma after repeated daily administration.
The incidence of ulcerative colitis in South Glamorgan during the decade 1968-77 remained steady with a mean of 7.2/10(5)/year. The disease was slightly more common in women, male:female ratio 1:1.2. Ulcerative colitis was rare in childhood but showed two peaks of incidence in adults, in the third and fourth decades and in the eighth decade.
A new approach to the problem of monitoring patients with chronic ulcerative colitis is presented and discussed in connection with a case report. When annual colonoscopies are performed, biopsies are taken for histopathological examination and DNA measurements are made using flow-cytometric techniques (FCM). Using the latter approach, gross chromosomal aberrations indicating malignant transformation in a cell population may be detected. In a 46 year old man with a long history of ulcerative colitis, an area with slight mucosal dysplasia at light microscopy was accompanied by two aneuploid cells lines - that is, colonic mucosa cells with an abnormal amount of DNA in the nuclei. An operation one year later revealed a 5 X 2 mm large adenocarcinoma in the corresponding area of the colon. We suggest that flow-cytometric techniques can be used as a complement to already practised methods for monitoring the colorectal mucosa in colitic patients for the early detection of malignancy.
The distribution of HLA A, B, C, DR antigens was investigated in a British population with ulcerative colitis. Fifty six patients were typed for HLA, A, B, C and 46 additionally for DR. No association was found between the HLA phenotype and the presence or absence of ulcerative colitis. Serum from 52 patients was tested for the presence of the anticolon antibody. There was no relation between the presence of the antibody and the HLA phenotype. Finally, no correlation was found between the HLA phenotypes, the age of onset of the disease, the extent and the clinical course.
It has been proposed that anti-inflammatory actions of corticosteroids rely on promotion of a natural peptide phospholipase A2 inhibitor, lipocortin, but in vivo effects on arachidonic acid metabolism have not been shown. Equilibrium dialysis of the rectum in patients with ulcerative colitis was used to determine whether cyclooxygenase and lipoxygenase products released from the inflamed rectal mucosa could be differentially inhibited by systemic treatment with prednisolone and indomethacin, respectively. In 10 patients with severe disease luminal concentrations of prostaglandin E2, prostaglandin F2 alpha, and leucotriene B4 were markedly raised (p less than 0.05) on comparison with 10 healthy controls, and they decreased significantly (p less than 0.05) within 72 hours after administration of prednisolone 1.5 mg/kg/day orally. In contrast prostaglandin, but not leucotriene B4 concentrations decreased (p less than 0.05) within 72 hours after administration of indomethacin 150 mg/day in another 10 patients with distal disease. These prompt reductions in concentrations of arachidonic acid metabolites more likely are caused by direct drug actions, rather than being secondary to decreased tissue damage. The data accord with the theory explaining anti-inflammatory effects of corticosteroids through lipocortin activity and support the belief that leucotrienes are more important than prostaglandins as mediators of inflammation in ulcerative colitis.
One hundred and sixty four patients with ulcerative colitis in remission were entered into a double blind, double dummy trial comparing olsalazine 500 mg bd and sulphasalazine 1 g bd. Clinical examination, sigmoidoscopy and rectal biopsy were performed at 0, three, and six months. Sixteen of 82 (19.5%) patients relapsed on olsalazine and 10/82 (12.2%) relapsed on sulphasalazine. The difference was not statistically significant (p = 0.1632). Adverse events were minor and were similar in both groups. No haematological or biochemical abnormalities were detected. Thus, olsalazine is as effective as sulphasalazine for preventing a relapse of ulcerative colitis.
To investigate local humoral immunity in ulcerative colitis (UC), immunoglobulin (Ig) contents and net Ig production in vitro was assessed using organ cultures of colonic biopsies from 21 patients with quiescent disease and 11 controls. Ig was estimated by enzyme linked immunoassay (ELISA) for IgA, secretory IgA (sIgA), IgM, and IgG. In parallel, numbers of IgA plasma cells were estimated by indirect immunoperoxidase staining of tissue sections for IgA. IgA was the dominant Ig isotype found pre-existing in colonic mucosae, and secreted in vitro. In UC patients, preformed tissue IgA and IgA produced in vitro were significantly increased compared with controls. There was no concomitant increase in amounts of sIgA synthesised in culture, however, although numbers of IgA plasma cells were increased in UC patients by an amount comparable with the increased in vitro IgA production. These results directly show a dysfunction of transepithelial IgA secretion in quiescent ulcerative colitis. Despite a significantly raised concentration of tissue IgG in UC patients, little was produced in vitro in patient and control groups alike, suggesting that mucosal IgG was serum derived, and not linked to local IgA production.
In a case-control study of smoking and ulcerative colitis patients with the disease were much less likely to smoke than community controls matched for age and sex. The difference was substantial, with an estimated relative risk of 3.8 for non-smoking on current habits, was even larger (6.2) when habits at onset of the disease were examined, and was mainly accounted for by 42 of 55 patients who had given up smoking a mean of eight years before onset. The association could not be explained by confounding by social class. These findings suggest that smoking directly or indirectly confers protection against ulcerative colitis.
The aim of this study was to determine the long-term outcome among 390 patients with ulcerative colitis who underwent ileal J pouch-anal anastomosis and whether patient or operative factors influenced results. The combined operative morbidity rate for the pouch-anal anastomosis and the subsequent closure of the temporary ileostomy was 29% (bowel obstruction, 22%; pelvic sepsis, 5%), with one death due to pulmonary embolus. The probability of a successful outcome at 5 years was 94%. Of the 24 patients who failed (6% of total), 18 did so within 1 year (4%), three during year 2 (1%), three during year 3 (1%), and none thereafter. Stool frequency (7 stools/24 h), the occurrence of pouchitis (14%), and satisfactory daytime continence (94% of patients) remained stable over 4 years after operation, whereas nocturnal fecal spotting decreased (51% of patients to 20%). Women had more spotting than men, whereas patients over 50 years old had more stools per day than those 50 years or younger. In conclusion, ileal pouch-anal anastomosis achieved a reasonable stool frequency and satisfactory continence in patients with ulcerative colitis over the long-term. These results support the ileal pouch-anal anastomosis as a safe, satisfactory alternative to permanent ileostomy.
Thirty-four patients with ulcerative colitis completed a double-blind assessment comparing the efficacy of two weeks of treatment with nightly retention enemas containing 3 g sulphasalazine or placebo. Symptom grading, sigmoidoscopic appearance, rectal biopsy specimens, and diary records were used to assess benefit and side effects. The active drug conferred significant benefit compared with placebo as shown by several criteria, but this benefit was confined to patients not already taking sulphasalazine by mouth. Overall assessment showed improvement in 11 of the 16 patients (70%) given the active treatment but in only two of the 18 (11%) given placebo. No side effects attributable to the drug were observed, even in patients previously intolerant to oral preparations. The logical therapeutic role of sulphasalazine enemas in ulcerative colitis would appear to be in patients who experience side effects such as nausea, abdominal discomfort, or headaches when taking the drug by mouth.
In six cases of idiopathic ulcerative colitis here reported, close correlation with emotional stress was shown. Psychosomatic relationship seemed definite. Experience with 85 patients with ulcerative colitis has led to the suggestion that emotional stress may be causative or a predisposing factor in some, perhaps all, such cases.
Comparative analysis of the systemic immunity revealed similarities between ulcerative colitis and idiopathic proctitis. In the active stage of both diseases, circulating complement receptor positive cells were increased whereas T-cell percentages and lymphocyte functions were decreased. In severe forms of ulcerative colitis and idiopathic proctitis circulating EAC-phagocytosing esterase positive cells, indicative of activated monocytes, were demonstrated. Successful treatment with salicylazosulfapyridine (SASP) reversed these immunological changes. Incubation of SASP and its metabolites with leucocytes from patients and control subjects, in concentrations similar to those demonstrated in sera from patients treated with SASP, did not alter the immunological changes.
Using a simple and rapid method, electrical potential differences across rectal and colonic mucosa have been measured at routine sigmoidoscopy in patients with irritable bowel syndrome and ulcerative colitis. In patients with irritable bowel syndrome, all of whom had diarrhoea, the mucosa was charged negatively on the luminal side and potential differences were not significantly different from those of normal subjects. In acute exacerbations of ulcerative colitis, the potential difference was reversed, the luminal side being positive. This characteristic change was seen even in mild attacks. The potential difference was usually restored to normal within a few weeks of commencing treatment. In some cases, however, it was persistently abnormal for months and failed to show the normal response to stimulation by the mineralocorticoid, fludrocortisone. The way in which measurements of potential difference can be useful in diagnosis, prognosis, and as a guide to treatment is discussed.
Sporadic colon carcinomas, carcinomas arising in chronic ulcerative colitis, and pancreatic adenocarcinomas have been analyzed for the presence of c-Ki-ras mutations by a combination of histological enrichment, cell sorting, polymerase chain reaction, and direct sequencing. Although 60% (37/61) of sporadic colon carcinomas contained mutations in codon 12, only 1 of 17 specimens of dysplasia or carcinoma from ulcerative colitis patients contained c-Ki-ras mutations, despite a high frequency of aneuploid tumors. In contrast, a higher percentage (16/20 = 80%) of pancreatic adenocarcinomas contained mutations in c-Ki-ras 2, despite a lower frequency of DNA aneuploidy in these neoplasms. Moreover, the spectrum of mutations differed between sporadic colon carcinoma, where the predominant mutation was a G to A transition, and pancreatic carcinomas, which predominantly contained G to C or T transversions. These results suggest that the etiology of ras mutations is different in these three human neoplasms.
The presence of anti-colon antibodies in sera from patients with ulcerative colitis was investigated with indirect haemagglutination and the fluorescent antibody procedure. The antigen was obtained from germ-free rats. There was a good correlation between the results obtained with both procedures.
A method is described of estimating retrograde spread through the colon of a 10% hydrocortisone acetate foam by labelling the foam with technetium-99m sulphur colloid and observing spread after intrarectal administration by serial gamma-camera pictures. The recommended 51 ml dose of foam reached the mid-sigmoid colon in all of the nine patients who had active ulcerative colitis. Furthermore, in seven the foam reached the proximal sigmoid colon. Foam spread less extensively in five patients with quiescent disease than in those with active disease. Increasing the volume of enema to 50 ml did not improve retrograde spread through the colon. These results suggest that 10% hydrocortisone foam may be useful in treating patients with distal ulcerative colitis that is not necessarily limited to the rectum.
BACKGROUND—K-ras mutation is one of the first genetic alterations in classical colorectal carcinogenesis. AIMS—To investigate the role of K-ras mutations in carcinogenesis, in long standing ulcerative colitis. METHODS—A total of 161 microdissected and 100 DNA samples from 13 patients were analysed for K-ras codons 12 and 13 mutations by means of a combination of enriched polymerase chain reaction amplification and temporal temperature gradient electrophoresis. RESULTS—K-ras mutations were found in 21/161 (13%) microdissected samples in 7/13 large bowels (16 and five in codons 12 and 13, respectively), and in 10/100 (10%) mucosal DNA samples (six and four, respectively). One of four patients with six adenocarcinomas had a K-ras mutation in a carcinoma, as well as one of two patients with large dysplasia associated lesion or mass (DALM). Eight of 13 (61%) areas with villous architecture and large, distended goblet cells, had a K-ras mutation, which was significantly more frequent than in low grade dysplasia (one of 23, 4%) but did not reach significance versus high grade dysplasia (four of 14, 28.5%). K-ras mutations were found in one of 20 (5%) flat lesions indefinite for dysplasia, two of 14 (14%) in non-villous...
BACKGROUND—Excessive mucosal generation of cytokines and eicosanoids has been reported in vitro in ulcerative colitis (UC) using traumatising biopsy techniques, and in vivo using time consuming rectal dialysis. AIMS—To validate a simple filter paper technique to profile rectal mucosal production of cytokines and eicosanoids in vivo in patients with UC compared with controls. PATIENTS—Forty one patients with UC (21 with active disease) and 16 controls were studied. METHODS—In vitro, recovery of known concentrations of cytokine or mediator applied to filter papers was measured by ELISA following incubation in buffer. In vivo, patients and controls had filter papers apposed to the rectal mucosa briefly through a rigid sigmoidoscope. Filter papers were then incubated prior to assay by ELISA. RESULTS—In vitro validation studies showed that the filter paper technique could be used to measure mucosal release of interleukin-1β (IL-1β), tumour necrosis factor α (TNF-α), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2), but not interferon γ (IFN-γ). Mucosal release of IL-1β, TNF-α, TXB2 and PGE2 were significantly increased in active UC (p=0.001) and correlated directly with disease activity (p=0.02). CONCLUSIONS—The filter paper technique confirmed increased rectal mucosal release of cytokines and eicosanoids in UC...