木瓜直播

A 56-year-old woman presents to the hospital after receiving positive findings on a fecal occult blood test (FOBT). She has no history of inflammatory bowel disease (IBD).

On questioning, she says that she has experienced general mild discomfort in her upper abdomen for the last several years. She denies having any abdominal pain, bloody mucoid diarrhea, or fever.

Physical abdominal exam is unremarkable aside from some mild tenderness in the right upper quadrant. Routine laboratory tests also return normal results except slightly elevated inflammatory markers: her erythrocyte sedimentation rate (ESR) is 58 mm/h and C-reactive protein (CRP) is 0.47 mg/dL.

A colonoscopy reveals localized inflamed and edematous mucosa from the ascending to the right-half of the transverse colon. The tissue shows mucosal friability with numerous shallow ulcerations, erosions, erythema, and loss of typical vascular patterns.

There is no evidence of patchy inflammation in other lesions or backwash ileitis. Stool culture finds no significant bacteria.

Biopsy of the inflamed colonic mucosa reveals infiltrations of chronic inflammatory cells in the lamina propria, cryptitis, crypt abscesses, and architectural glandular distortions. However, there is no evidence of epithelioid granulomas. Furthermore, colonoscopy of the rectum and left-sided colon returned intact findings with no histological evidence of inflammation.

Based on these findings, clinicians diagnose the patient with right-sided ulcerative colitis (UC). Disease activity is a score of 3 on the Mayo scoring system.

Treatment with mesalamine 2,400 mg/day is initiated.

The patient develops a slight fever about 1 week later, which periodically increases to over 39 °C. however, she does not experience any abdominal pain or worsening of diarrhea.

Sixteen days after beginning mesalamine treatment, the patient is admitted to the hospital.

On admission, a physical is performed that – as in her initial examination – finds that the patient has a high fever and mild tenderness of the right upper quadrant. However, she has no other abdominal symptoms or signs of a drug allergy, such as a skin rash.

Blood test results show increased levels of inflammation, but no evidence of eosinophilia (4% of 5.73 × 10⁹/L white blood cells) or elevations in liver or pancreatic enzymes. ESR is 119 mm/h and CRP level is 18.3 mg/dL. Serum procalcitonin is also normal, and blood culture for cytomegalovirus (CMV) antigenemia are negative, so clinicians rule out infections as a possible cause of her symptoms.

Tests for anti-nuclear antibody (ANA) and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) are also negative. However, the patient is positive for proteinase-3 ANCA (PR3-ANCA) at 55.2 U/mL by CLEIA method.

When magnetic resonance cholangiopancreatography (MRCP) did not identify primary sclerosing cholangitis (PSC), clinicians suspect the patient is having mesalamine-induced hypersensitivity reactions.

A lymphocyte transformation test (LTT) for mesalamine has a positive result (220 cpm, 207% of control). Based on this, the patient is diagnosed with right-sided or segmental colitis type UC concomitant with mesalamine-induced hypersensitivity reactions.

Treatment and Outcome

Clinicians immediately discontinue mesalamine treatment. A second colonoscopy reveals more intensely inflamed mucosa in the locations at the same colonic segments noted in the first colonoscopy, from the ascending colon to the right-half of the transverse colon.

However, symptoms are worsening, with evidence of more edematous mucosa, bowel stenosis, and much more purulent erosions and ulcerations. As well, the mucosal inflammation is expanding toward the oral and anal sides. There are also scattered erosions in the cecum and around the appendiceal orifice and in the left-half of the transverse colon.

While the biopsy specimen of this sample of the inflamed mucosal tissue confirms an increasing inflammation, the left-sided colon from the descending colon to the rectum remains free of evidence of inflammation.

The fever and inflammatory findings quickly resolve when the mesalamine is stopped. At this point, clinicians manage the patient with probiotics Bifidobacterium longum and B. infantis alone.

The patient is discharged from the hospital. However, in follow up visits, she continues to report vague discomfort on the right side of her upper abdomen. About 3 months after cessation of mesalamine, she undergoes a third follow-up colonoscopy. This reveals some amelioration of the inflammation, which is restricted again to the area from the ascending colon to the right-half of the transverse colon.

Improvement is also noted in the edematous mucosa and the bowel stenosis of the inflamed section of the colon. As well the ulcerations observed in the ascending colon are now ulcer scars, and the purulent erosions and shallow ulcerations have improved.

Scattered erosions at the cecum and the left-half of the transverse colon noted in the second colonoscopy are no longer evident. With clearing of the edematous mucosa, the border between the inflamed and non-inflamed mucosa at the right-side of the transverse colon is now clear.

At this point, clinicians augment the probiotic treatment with oral prednisolone 30 mg/day and 6-mercaptopurine (6-MP) at 30 mg/day, and the steroid dose is tapered gradually over a one-year period.

Body temperature and ESR improved immediately after the withdrawal of mesalamine. In particular, ESR improved after the introduction of prednisolone and 6-MP.

Case Follow-up

Three months later, a fourth colonoscopy reveals further improvement of the edema of the inflamed mucosa from the ascending to the right-half of the transverse colon had improved even more and disappeared, to the extent that it has resolved and only multiple reticular scars remain. The active erosions and ulcers are no longer evident. Instead, there is evidence of regenerating epithelium at the same colonic segment.

The border between the inflamed and non-inflamed mucosa at the right-side of the transverse colon can be seen more clearly. As well, there are improvements in the ESR (17 mm/h) and CRP (0.03 mg/dL). The patient continues to be in good general condition following her discharge from the hospital.

Discussion

Clinicians report a rare of right-sided ulcerative colitis with mesalamine-induced aggravation with unusual overlapping clinical features, which was diagnosed after a positive finding on a routine FOBT.

The case was complicated by mesalamine-induced hypersensitivity reactions also describe the evolving endoscopic findings related to the hypersensitivity reactions to mesalamine.

While ulcerative colitis-related inflammation is generally confined to the mucosal layers of the bowel continuously from the rectum to the proximal side, some cases of proctitis or left-sided colitis with a cecal patch of inflammation and UC with right-sided or segmental colitis with no recto-sigmoid inflammation has been reported.

UC is typically treated with mesalamine and other 5-aminosalicylic acid (5-ASA) compounds because of their safety and effectiveness. However, hypersensitivity reactions to mesalamine can occur and cause aggravation of UC.

While UC typically involves the rectum with extension to the proximal colon in a continuous manner, involvement of the appendiceal orifice as a discontinuous lesion is well known.

In Japan's diagnostic and therapeutic guidelines in 2017, the right-sided or segmental type of UC is classified as one disease type along with total, left-sided colitis, and proctitis, case authors note. To date, this subtype of UC in which the anal side is spared has been described in very few reports from Western countries.

Although the cause of this discrepancy is not well understood, the subgroup of patients with an uncertain diagnosis are classified as "indeterminate colitis," a diagnosis that accounts for about 5% of inflammatory bowel disease cases in Japan.

The atypical location of the colonic lesion in the present case could fit this classification, except that the colonic lesion was not only restricted to the right side of the colon, it was continuous. There were no lesions suggestive of Crohn's disease, such as longitudinal ulcers and a cobblestone appearance. Moreover, the histological lesions showed typical features of UC, without any granulomatous lesions, leading to the diagnosis of UC in this patient.

ANCAs are the most frequently studied serological markers for IBD. Case authors note that the present case was negative for MPO-ANCA, which constitutes a large part of P-ANCA, but was positive for PR3-ANCA, which targets the serine protease.

Authors note that PR3-ANCA positivity has been reported to help differentiate UC from CD. However, the data remain mixed, and were called into question recently by results of an Australian retrospective, cross-sectional study. Researchers Lee, et al. found that in their cohort of 2,550 patients, more than 80% of the IBD patients who underwent ANCA testing had a result and a significant proportion had positive PR3 antibodies. However, no specific ANCA pattern predicted a specific IBD subtype or clinical course, they reported. As well, these researchers found that pairing ANCA and anti-Saccharomyces cerevisiae (ASCA) did not add value in subtyping IBD for these patients, suggesting there is little value in ordering an ANCA for patients with IBD.

Case authors noted that the on their case is strongly supported by data showing that a cutoff PR3-ANCA titer of 11.8 chemiluminescent units has 97.3% specificity for UC (it was 55.2 in the present case). Although PR3- ANCA is frequently detected in primary sclerosing cholangitis, this disease was not detected with MRCP, they added.

Case authors noted that fecal occult blood screening for colorectal cancer appears to have some utility in detecting UC, including right-sided or segmental colitis type in healthy individuals, according to one report. Among 44,838 cases that were FOB-positive on screening for colorectal cancer, 52 were previously undetected UC. This yields an estimated rate of 116 per 100,000 and 17% (9/52) were asymptomatic. Among them, 52% (27/52) had only proctosigmoiditis, and 25% (13/52) had total colitis. However, this series did not detect any cases of right-sided or segmental colitis type of UC.

On the other hand, among 236,000 healthy Japanese patients who underwent FOB test screening, 19 were diagnosed as having asymptomatic or minimally symptomatic UC on colonoscopy, and four had asymptomatic right-sided or segmental type, case authors wrote.

They noted that 5-ASA agents such as mesalamine are considered safe and are first-line treatments for inducing remission and preventing UC. Nevertheless, this case highlights the importance of vigilance for the potential disease-aggravating effects of hypersensitivity reactions to mesalamine, including fever and rash in some patients.

They added that while aggravation of UC with mesalamine has also been reported, there have been very few reports of the changes in the endoscopic findings caused by hypersensitivity reactions. In this patient, more edematous mucosa, much more purulent erosions, and ulcerations were seen. However, it is interesting that, despite some extensions of lesions to both oral and anal sides, the left-sided colon remained intact.

The diagnosis of mesalamine-induced aggravation was based on the dramatic amelioration of symptoms after cessation of the drug, and confirmed by the positive LTT result. To the best of our knowledge, this is the first report to show changes in the endoscopic findings during mesalamine- induced hypersensitivity reactions in a case of right-sided colitis type of UC.

References

1. H Hirono, et al: A Case of Right-Sided Ulcerative Colitis with Mesalamine-Induced Hypersensitivity Reactions. Am J Case Rep 2018; 19: 623-629

2. Conrad K, et al: Diagnosis and classification of ulcerativecolitis. Autoimmun Rev 2014; 13: 463–66

3. Ordas I, et al: Ulcerative colitis. Lancet 2012; 380: 1606–19.

4. Rubin DT, Rothe JA: The peri-appendiceal red patch in ulcerative colitis: Review of the University of Chicago experience. Dig Dis Sci 2010; 55: 3495–501

5. Cohen T, et al: "Ulcerative appendicitis" occurring as a skip lesion in chronic ulcerative colitis; Report of a case. Am J Gastroenterol 1974; 62: 151–55

6. Kurt EJ, Brown CH: Segmental ulcerative colitis, classification; Report of nine unusual cases. Am J Gastroenterol 1959; 31: 419–31

7. Okada M, et al: Right-sided ulcerative colitis. J Gastroenterol 1996; 31: 717–22

8. Ford AC, et al: Efficacy of 5-aminosalicylates in ulcerative colitis: Systematic review and meta-analysis. Am J Gastroenterol 2011; 106: 601–16

9. Kapur KC, et al: Mesalazine induced exacerbation of ulcerative colitis. Gut 1995; 37: 838–39

10. Sturgeon JB, et al: Exacerbation of chronic ulcerative colitis with mesalamine. Gastroenterology 1995; 108: 1889–93

11. Tremaine WJ: Is indeterminate colitis determinable? Curr Gastroenterol Rep 2012; 14: 162–65

12. Quinton JF, et al: Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: Prevalence and diagnostic role. Gut 1998; 42: 788–91

13. Lee, Wei-I, et al: The significance of ANCA positivity in patients with inflammatory bowel disease. Pathology 2019 (51) 6: 634 – 639

14. Arias-Loste MT, et al: Presence of anti-proteinase 3 antineutrophil cytoplasmic antibodies (anti-PR3 ANCA) as serologic markers in inflammatory bowel disease. Clin Rev Allergy Immunol 2013; 45: 109–16

15. Stinton LM, et al: PR3-ANCA: A promising biomarker in primary sclerosing cholangitis (PSC). PLoS One 2014; 9: e112877

16. Howarth GF, et al: High prevalence of undetected ulcerative colitis: Data from the Nottingham fecal occult blood screening trial. Am J Gastroenterol 2002; 97: 690–94

17. Sakata T, et al: Asymptomatic inflammatory bowel disease with special reference to ulcerative colitis in apparently healthy persons. Am J Gastroenterol 2001; 96: 735–39

18. Marteau P, et al: Adverse events in patients treated with 5-aminosalicylic acid: 1993–1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther 1996; 10: 949–56

19. Ding H, et al: Ulcerative colitis flair induced by mesalamine suppositories hypersensitivity. World J Gastroenterol 2014; 20: 3716–18

20. Gupta MK, et al: Mesalamine induced symptom exacerbation of ulcerative colitis: Case report and brief discussion. World J Gastrointest Pharmacol Ther 2010; 1: 132–34

21. Shimodate Y, et al. Exacerbation of bloody diarrhea as a side effect of mesalamine treatment of active ulcerative colitis. Case Rep Gastroenterol 2011; 5: 159–65

22. Pichler WJ, Tilch J: The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004; 59: 809–20

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