A case of sequential development of celiac disease and ulcerative colitis
William Dickey About the author
Correspondence Department of Gastroenterology, Altnagelvin Hospital, Londonderry BT47 6SB, Northern Ireland, UK
Email wildickey@aol.com
Summary
Background A 65-year-old white female who presented with flatulence and weight loss was investigated by celiac antibody testing, esophagogastroduodenoscopy, duodenal biopsy and colonoscopy. There were no positive findings, except for diverticulosis. Almost 5 years later repeat investigations performed in response to the patient's anemia confirmed the development of celiac disease. After 18 months of symptom improvement as a result of gluten exclusion the patient developed diarrhea, and colonoscopy revealed ulcerative colitis.
Investigations Physical examination; analysis of full blood count; measurement of serum ferritin, vitamin B12, folate and C-reactive protein levels; thyroid and autoantibody profiling (including analysis of endomysial and tissue transglutaminase antibodies); CT scanning of the chest, abdomen and pelvis; and performance of esophagogastroduodenoscopy, push enteroscopy, colonoscopy and wireless capsule endoscopy.
Diagnosis Celiac disease and ulcerative colitis.
Management Gluten-free diet, mesalazine and prednisolone.
Keywords:
biopsy, celiac disease, diagnosis, serology, ulcerative colitis
The case
A 65-year-old white female presented to a gastroenterology clinic with a 3-month history of excess flatulence/flatus, and weight loss of 9.5 kg (21 lbs) in the preceding 12 months. Her medical history was otherwise unremarkable; she reported no abdominal pain, alteration in bowel habit or hemochezia. She denied a family history of colon neoplasia, celiac disease, Crohn's disease or ulcerative colitis. Physical examination did not reveal anything of note.
Initial laboratory investigations revealed that the patient had a normal hemoglobin concentration with normal levels of serum ferritin, vitamin B12, folate, C-reactive protein (CRP) and thyroxine and thyroid-stimulating hormone. Her erythrocyte sedimentation rate (ESR) was also normal. An autoimmune profile of the patient, which included tests for antinuclear, antinucleolar, anti-smooth-muscle and antimitochondrial antibodies, was negative. The patient's serum was negative for endomysial antibody (EmA), as measured by indirect immunofluorescence in an assay that used primate esophagus substrate (Biodiagnostics, Upton-upon-Severn, UK). The patient's tissue transglutaminase antibody (TTGA) level, measured by use of a guinea pig antigen-based enzyme-linked immunosorbent assay (ELISA; Immco Diagnostics, Buffalo, NY, USA), was 8 ELISA units (normal level 0–25 ELISA units).
No abnormalities were revealed by esophagogastroduodenoscopy. Assessment of four forceps biopsy samples obtained from the descending duodenum of the patient, in order to look for evidence of celiac disease, revealed normal intraepithelial lymphocyte counts and normal villous height (Figure 1). A colonoscopy was performed and reached the terminal ileum and findings were normal except for sigmoid diverticulosis. CT scans of the chest, abdomen and pelvis were also normal. During the initial follow-up period, the patient's weight stabilized, her symptoms responded to treatment with an antispasmodic (mebeverine, 135 mg three times daily), and she was discharged back to the care of her general practitioner.
Figure 1 Histologic image of a duodenal biopsy sample from the case patient, obtained soon after the initial presentation.
No evidence of celiac disease can be seen—intraepithelial lymphocyte counts are normal and villi are of normal height.
Full figure and legend (49K)Figures & Tables indexDownload Power Point slide (94K)The patient was referred back to the gastroenterology clinic approximately 5 years later, after having presented to her general practitioner with a 6-month history of fatigue; she did not report any other symptoms. A low concentration of hemoglobin in the patient's blood (115 g/l; normal concentration >125 g/l) had prompted her general practitioner to request celiac serology tests. The results of celiac serology revealed that the patient's serum was positive for EmA and contained an abnormal level of TTGA (54 ELISA units). No abnormalities were seen when the patient underwent push enteroscopy to the jejunum. Biopsy samples obtained from the patient's duodenum confirmed the presence of villous atrophy with crypt hyperplasia and increased numbers of intraepithelial lymphocytes (Figure 2). No histologic abnormalities were found in jejeunal biopsy samples. The patient declined repeat colonoscopy. CT scans of her chest, abdomen and pelvis were normal.
Figure 2 Histologic image of a duodenal biopsy sample from the case patient obtained at the patient's second presentation, almost 5 years after the initial presentation.
Villous atrophy, crypt hyperplasia and an increased number of intraepithelial lymphocytes can be seen.
Full figure and legend (48K)Figures & Tables indexDownload Power Point slide (92K)Additional blood work revealed that the patient had a low serum ferritin level (38 pmol/l [17 ng/ml]; normal value >58 pmol/l [>26 ng/ml]) indicative of iron deficiency; however, the ESR and levels of B12, folate and CRP were normal. A dual X-ray absorptiometry scan revealed that the patient had osteoporosis in the lumbar spine and osteopenia in the left femur. It was concluded that her anemia and osteoporosis were the result of celiac disease. The patient began a gluten-free diet under dietetic supervision. She began maintenance treatment with daily calcium and vitamin D supplements and weekly oral alendronic acid (70 mg) for her reduced bone density. Within 6 months she was asymptomatic, her hemoglobin concentration had risen to 134 g/l without the need for iron supplements, and her celiac serology had reverted to normal.
Approximately a year later (6.5 years after her initial presentation) the patient reported diarrhea for the first time. She underwent colonoscopy that revealed granular, erythematous mucosa with multiple ulcers, distributed continuously from the rectum to the splenic flexure (Figure 3). Histologic analysis of biopsy samples revealed a chronic inflammatory infiltrate, with ulceration, cryptitis and crypt abscess formation and no granulomata, consistent with a diagnosis of ulcerative colitis. At this time the patient's hemoglobin concentration had fallen to 97 g/l, her ESR was 90 mm/h, her CRP concentration was 165 mg/l (normal concentration <8 mg/l) and her celiac serology remained negative.
Figure 3 Image obtained from colonoscopy performed after the patient's third presentation, 6.5 years after her initial presentation.
Granular, erythematous mucosa with multiple ulcers can be seen, consistent with active ulcerative colitis.
Full figure and legend (20K)Figures & Tables indexDownload Power Point slide (64K)Duodenal biopsy results showed complete villous recovery with no excess of intraepithelial lymphocytes, and wireless capsule endoscopy revealed no pathology elsewhere in the small bowel. Although the patient's diarrhea settled initially when she was prescribed oral mesalazine (1,000 mg twice daily) as maintenance therapy, she relapsed with diarrhea and hemochezia 3 months later. A course of oral prednisolone (commenced at a dose of 40 mg daily and reduced progressively over an 8 week period) was required to achieve satisfactory remission once again, after which oral mesalazine successfully maintained remission during an additional 12 months of follow-up. The patient remains under review at a specialist celiac clinic.
Discussion of diagnosis
Celiac disease is an autoimmune enteropathy primarily affecting the proximal small bowel and triggered in genetically susceptible individuals by exposure to wheat, barley and rye gluten. Over 90% of patients with celiac disease express the major histocompatibility complex human leukocyte antigen (HLA) DQ2 haplotype and most of the rest express HLA-DQ8.1 The findings of screening studies indicate that celiac disease affects around 0.5–1.0% of members of populations with European ancestry, which includes members of the US population.2 Gluten enteropathy comprises a spectrum of histologic abnormalities that affect the duodenum and jejunum; the enteropathy was first described by Marsh (later modified by Oberhuber and co-workers).3 Marsh I enteropathy is defined by an excess of intraepithelial lymphocytes (>30 per 100 enterocytes), Marsh II enteropathy has, in addition, the presence of crypt hyperplasia, and Marsh III enteropathy is the 'classic' celiac lesion, which comprises Marsh I and Marsh II enteropathy plus villous atrophy. Most patients with celiac disease test positive for serum EmA and TTGA, which enables initial tests for celiac disease to be performed by physicians other than gastroenterologists; however, false-negative results occur in 10% of patients or more4 and duodenal biopsy samples should be obtained for assessment if a diagnosis of celiac disease is suspected.
Clinical presentation of celiac disease
The traditional perception of celiac disease is one of childhood onset and presentation with symptoms directly attributable to malabsorption, which include steatorrhea and weight loss. Nonetheless, despite ingesting gluten since infancy most patients are diagnosed in adulthood; in one Italian study 4% of patients were diagnosed when they were over 65 years of age.5 For many cases in the past, diagnosis in adulthood reflected a failure on the part of clinicians to consider a diagnosis of celiac disease, resulting in delayed diagnosis despite the presence of symptoms for many years.5, 6 Only a minority of cases have the typical clinical presentation owing to malabsorption. Patients are frequently overweight at presentation6, 7 and in one unit, fewer than a third of patients reported diarrhea as a symptom at presentation.4 Patients can present with nonspecific gastrointestinal symptoms including dyspepsia and reflux, or with non-gut symptoms including anemia, chronic fatigue, peripheral neuropathy and ataxia.
The histologic changes that accompany the development of gluten enteropathy might develop for the first time in later life. Around 10% of patients who test positive for serum EmA have no, or only mild (Marsh I) enteropathy, which if left untreated will proceed to villous atrophy in most cases.8 Sanders et al. describe the case of a 79-year-old male who, despite having symptoms of celiac disease, had negative serological test results and histology. In spite of these negative results, the disease progressed to strongly positive serology and total villous atrophy within 3 months.9
The case patient's initial symptoms of flatulence and weight loss prompted investigation for celiac disease by serological testing and duodenal biopsy; the findings from both investigations were initially negative, and positive results were obtained only after the onset of iron-deficiency anemia. Negative investigations for celiac disease do not preclude its diagnosis later in life. HLA-DQ typing, which was unavailable at the facility handling this case, can determine which patients are HLA-DQ2 and HLA-DQ8 negative and are, therefore, unlikely to develop celiac disease in the future.1 Research has shown that a 'trigger'—often unidentified—is required to precipitate the onset of clinical celiac disease—pregnancy and the puerperium are the best documented examples.10
Failure to respond to a gluten-free diet
Patients with celiac disease can fail to respond to the initial introduction of a gluten-free diet or have a recurrence of symptoms after initial improvement, despite maintaining gluten exclusion. The most feared causes of either scenario are complicating malignancy, notably enteropathy-associated T-cell lymphoma, or refractory sprue, which is defined as the failure of a gluten-free diet to restore normal small-bowel architecture and function. Both of these complications are associated with considerable morbidity and mortality.11 Assuming that the initial diagnosis of celiac disease is correct, continued deliberate or inadvertent gluten ingestion should be stopped. Other causes of persistent symptoms with increased prevalence in celiac disease include lactose intolerance, exocrine pancreatic insufficiency, bacterial overgrowth and microscopic (lymphocytic or collagenous) colitis.12, 13
Initially, the case patient's celiac disease responded well to gluten exclusion, as shown by the resolution of her symptoms, the recovery of her hemoglobin level and the disappearance of EmA and TTGA from her serum; in addition, subsequent follow-up confirmed the absence of histologic abnormalities in duodenal biopsy samples. Enteroscopy and CT scanning did not detect evidence of lymphoma on diagnosis of celiac disease. Subsequent wireless capsule endoscopy, which is a valuable imaging technique for the diagnosis of small-bowel tumors, also did not detect evidence of lymphoma.14 There was no evidence of collagenous or lymphocytic colitis in the patient's colon histology, and her response to active treatment of ulcerative colitis and maintenance of gluten exclusion avoided the need to carry out investigations for pancreatic insufficiency, lactose intolerance and bacterial overgrowth.
Colon pathology in patients with celiac disease
The association between celiac disease and microscopic colitis (either collagenous or lymphocytic) is well recognized. In addition, Yang et al.15 reported that the prevalence of ulcerative colitis and Crohn's disease was significantly higher among patients with celiac disease than in the general population (prevalence rate ratios of 3.6 and 8.5, respectively). In 5 out of 10 patients with both celiac disease and IBD the diagnosis of celiac disease preceded that of IBD (by 7 months to 12 years); in addition, the symptoms of 4 of these 5 patients were improved by a gluten-free diet, which suggests that gluten is not the trigger for IBD in patients with celiac disease. Similarly, the case patient had excellent clinical, serological and histologic improvement of celiac disease before the onset of her ulcerative colitis symptoms. Finally, while there is no firm evidence to support an association between celiac disease and colonic neoplasia, both conditions are common and can coexist by chance in older patients.16 Colonoscopy should, therefore, be part of the initial work-up in patients who are 40 years of age or older who present with iron-deficiency anemia or diarrhea, even if initial tests indicate celiac disease.
Treatment and management
The mainstay of treatment for celiac disease remains a gluten-free diet administered under the supervision of an experienced dietician. Nutritional deficiencies should be identified and treated by supplementation if necessary pending a response to gluten exclusion. A dual X-ray absorptiometry scan is mandatory in elderly patients with celiac disease, and osteoporosis should be treated with calcium, vitamin D and bisphosphonates. No evidence exists to suggest that ulcerative colitis symptoms, which might be present in conjunction with celiac disease, improve as a result of gluten exclusion. The case patient was prescribed mesalazine as maintenance therapy and steroids (oral prednisolone) to treat relapse and re-establish remission of her ulcerative colitis.
Conclusions
Patients can develop, or present with, celiac disease at any stage in life. Previous negative test results do not preclude the diagnosis of celiac disease at a later date. The possibility of additional pathology should be considered, particularly in older patients whose symptoms fail to respond, or who later relapse, despite the exclusion of gluten from their diet. Diarrhea and anemia, in particular, should prompt colonoscopy. In patients with celiac disease there is an increased prevalence of not only microscopic colitis, but also ulcerative colitis and Crohn's disease.
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Competing interests
The author is an unpaid member of the Medical Advisory Council of Coeliac UK.
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Subject areas under which this article appears: Small intestine | Nutrition
