Celiac Disease and Sprue Spectrum: Celiac Disease and Sprue Spectrum: When Diet Fails

0:00Welcome to Board Pearls. This is episode two of two of the Celiac Disease and Sprue Spectrum chapter, in the Stomach and Small Bowel Disorders module. This episode is the celiac patient who doesn't get better on the diet. One man goes through the workup in order. His case shows how hidden gluten is looked for, why the original diagnosis is checked, which other conditions cause the same diarrhea, and which drugs imitate the disease. Only then is refractory celiac disease considered, and his case shows how it's proven, why its two types differ so sharply in outcome, and which cancers to watch for. Most patients like him don't turn out to be refractory, which is why the order matters.

0:40Here's the patient. A sixty-one-year-old man was diagnosed with celiac disease three years ago, with villous atrophy and a strongly positive tissue transglutaminase antibody. He improved at first on a gluten-free diet, and his antibody normalized within a year. For the past six months, though, he's had watery diarrhea several times a day, and he's lost eighteen pounds. He insists he's strict.

1:04He has non-responsive celiac disease, ongoing or recurring symptoms despite twelve months of a gluten-free diet. It's common, and its differential is worked through in order of likelihood, because most causes are fixable and only a few are dangerous.

1:18The likeliest cause is that he's still eating gluten. Intentional non-adherence, cross-contamination, and gluten hidden in processed foods, medications, and supplements account for most non-responsive patients, including many who believe they're strict.

1:34So the first step, in every non-responsive patient, is a review by a dietitian experienced in celiac disease. A persistently positive antibody is the usual sign of ongoing exposure. His antibody is normal, but that doesn't settle it, because serology and histology can disagree, and a normal antibody doesn't prove the bowel has healed. His dietitian goes through his kitchen, his restaurant habits, his medications, and his supplements, and finds no source of gluten.

2:05With gluten excluded, the next question is whether he had celiac disease at all. A patient labeled celiac on the basis of a positive antibody alone, or raised lymphocytes alone, may never have had it, and then the diet was never going to fix his symptoms. So the original diagnosis is confirmed from three sources: the original serology, human leukocyte antigen, HLA, typing for DQ2 or DQ8, and an expert review of the original biopsies. His original antibody was strongly positive, his original biopsies showed clear villous atrophy on expert review, and he carries DQ2. His diagnosis was right.

2:43A correct diagnosis means something else may be causing his diarrhea, because celiac patients are prone to several conditions that cause the same symptoms. Microscopic colitis is fifty to seventy times more common in celiac disease than in the general population, and it causes watery diarrhea even when the duodenum has healed. So colonoscopy with random biopsies, even from normal-looking mucosa, is part of his workup.

3:09The other coexisting causes each have a simple test. Pancreatic exocrine insufficiency is checked with fecal elastase, and a level under two hundred micrograms per gram calls for enzyme replacement. Small intestinal bacterial overgrowth is checked with a breath test or an empiric course of rifaximin. Lactose or fructose intolerance, irritable bowel syndrome, and inflammatory bowel disease, IBD, especially Crohn disease of the small bowel, are considered too.

3:38A drug can also imitate his disease, so his medication list is reviewed carefully. Some drugs damage the small bowel and produce villous atrophy that looks just like active celiac disease: olmesartan and other angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, NSAIDs, and mycophenolate. For him, colonoscopy with random biopsies is normal, fecal elastase is normal, a breath test is negative, and he takes no culprit drugs.

4:07Only now can refractory celiac disease be considered. It's persistent or recurrent malabsorptive symptoms with villous atrophy despite at least twelve months of a strict gluten-free diet, with no other explanation. It affects about one to two percent of celiac patients, up to five percent in some referral centers. It matters far beyond its frequency, because one type is essentially a precursor of lymphoma.

4:31Proving it depends on how the biopsies are handled. He has a repeat endoscopy with up to six more duodenal biopsies. Two or three go fresh into saline or culture medium for flow cytometry. Two or three go into formalin for immunohistochemistry and a polymerase chain reaction, PCR, test for T-cell receptor gene rearrangement.

4:52The container matters because formalin destroys the surface markers that flow cytometry reads, and those markers define the two types. If every biopsy goes into formalin, the most important test can't be done. Immunohistochemistry and the rearrangement study add information about whether the lymphocytes are a single clone.

5:11The intraepithelial lymphocytes decide which type he has. In refractory celiac disease type one, the lymphocytes are polyclonal and look normal. They carry surface CD3 and CD8, and abnormal lymphocytes make up less than twenty percent. In type two, abnormal lymphocytes make up more than twenty percent. They've lost surface CD3 and CD8 but still contain CD3 inside the cell, and the T-cell receptor rearrangement is monoclonal, meaning a single clone has taken over.

5:43His biopsies show persistent total villous atrophy. Flow cytometry shows that thirty-five percent of the intraepithelial lymphocytes lack surface CD3 and CD8, and the T-cell receptor rearrangement is monoclonal. He has refractory celiac disease type two.

6:05His type decides his treatment, because the two types have very different outlooks. Type one behaves like a more stubborn form of ordinary celiac disease. Treatment is the strict diet plus budesonide, nine milligrams a day, given as three milligrams three times daily, with the enteric-coated capsules opened so the drug reaches the small bowel.

6:21Type one has several second-line options and a good outlook. They're prednisone at half to one milligram per kilogram a day; a thiopurine after thiopurine methyltransferase, TPMT, testing, either azathioprine two to two and a half milligrams per kilogram a day or six-mercaptopurine one to one and a half; or infliximab. Five-year survival is over ninety percent, and progression to lymphoma is uncommon, around fourteen percent over five years.

6:51Type two, his type, is essentially a low-grade T-cell lymphoma in waiting, with a five-year mortality around fifty percent. Treatment starts with the diet and steroids or budesonide for symptoms, but those don't touch the clone. The treatment that targets the abnormal clone is cladribine, a purine analog, often followed by autologous stem cell transplant in fit patients to consolidate the response. Fludarabine is an alternative. Many patients need parenteral nutrition, because the malabsorption is severe.

7:21He starts cladribine and is referred for transplant evaluation. He's also started on nutritional support for his weight loss.

7:28Type two is dangerous because of what it becomes. Enteropathy-associated T-cell lymphoma arises from type two refractory disease in essentially every case, and it develops in a third to a half of type two patients within five years. It's uncommon overall but six to nine times more frequent in celiac disease. It's high grade, usually in the jejunum but sometimes in the ileum, often multifocal and ulcerating. It peaks in the seventh decade and is more common in men.

7:58It presents as an apparent relapse. A stable patient develops worsening diarrhea, weight loss, abdominal pain, fevers, or unexplained anemia. So when a patient relapses on a strict diet, three explanations are held in mind together: gluten, refractory disease, and lymphoma.

8:16Finding it takes small bowel imaging and tissue. The tests are computed tomography, CT, or magnetic resonance, MR, enterography; capsule endoscopy, which is especially good at showing multifocal ulcers and masses; and balloon-assisted enteroscopy to biopsy them. Treatment is anthracycline-based chemotherapy, similar to cyclophosphamide, doxorubicin, vincristine, and prednisone, CHOP, with autologous transplant in fit patients. The prognosis is poor, with survival at thirty months around thirteen percent.

8:48A related complication shares his clone. Ulcerative jejunitis, also called ulcerative jejunoileitis, is multiple chronic ulcers in the jejunum and upper ileum, with strictures, bleeding, perforation, or obstruction. It carries the same abnormal T-cell clone as type two disease and often coexists with or comes before the lymphoma. It presents with pain, bleeding, or obstruction in a patient on a strict diet, it's found by capsule or enteroscopy, and it's treated like type two, with cladribine and transplant, plus surgery for complications.

9:25The other celiac-associated cancer behaves differently, and that changes who's at risk. Small bowel adenocarcinoma is several times more common than in the general population, and it can arise even in well-controlled disease, without refractory disease first. It's usually jejunal and presents with obstruction or iron deficiency from slow blood loss. It's found with CT enterography, capsule, or double-balloon enteroscopy, and treated with resection and chemotherapy. B-cell non-Hodgkin lymphoma and squamous cancers of the throat and esophagus are modestly more common too.

10:01Those cancers set who needs surveillance. Uncomplicated celiac disease needs no cancer screening beyond the usual age-based tests and the healing biopsy at about two years, and strict adherence to the diet lowers the cancer risk. Surveillance with cross-sectional imaging and capsule endoscopy is added in two situations: type two refractory disease, like his, and unexplained worsening in a previously stable patient.

10:27So he'll have small bowel imaging and capsule endoscopy as part of his follow-up. Any new fever, pain, bleeding, or weight loss means looking for lymphoma.

10:38Poorly controlled celiac disease also leaves damage that isn't cancer. It includes deficiencies of iron, B12, folate, vitamin D, calcium, the fat-soluble vitamins, copper, and zinc; bone disease with more fractures; unexplained liver enzyme elevation that can progress to celiac-associated liver disease; and infertility and pregnancy loss. The associated autoimmune diseases, autoimmune thyroid disease, autoimmune hepatitis, primary biliary cholangitis, and type one diabetes, add to the burden. So strict adherence does more than control symptoms, because it lowers the long-term risk of fracture, cancer, and reproductive problems.

11:21Here are the traps the boards set in this patient. A patient isn't called refractory before a dietitian has checked for gluten exposure. A normal antibody doesn't prove the bowel has healed. The original diagnosis is confirmed with serology, HLA typing, and an expert biopsy review. And microscopic colitis, pancreatic insufficiency, bacterial overgrowth, and olmesartan aren't missed.

11:45The refractory disease traps close the list. The biopsies don't all go in formalin, because flow cytometry needs fresh tissue. Type two isn't treated like type one. Budesonide capsules are opened for small bowel disease. And a relapse in a stable patient isn't blamed on gluten without considering lymphoma.

12:04So, start to finish. Most non-responsive celiac disease is ongoing gluten exposure, so check that first with a dietitian. Then confirm the original diagnosis, then look for microscopic colitis, pancreatic insufficiency, bacterial overgrowth, sugar intolerance, IBD, and drugs such as olmesartan.

12:24Refractory celiac disease requires persistent villous atrophy and symptoms after twelve months of a strict diet. Type it by flow cytometry on fresh biopsies. Type one has normal polyclonal lymphocytes, responds to open-capsule budesonide, and has an excellent five-year survival.

12:41Type two has more than twenty percent abnormal lymphocytes lacking surface CD3 and CD8, with a monoclonal rearrangement. It's a lymphoma precursor, treated with cladribine and transplant.

12:53A relapse in a stable patient can be enteropathy-associated T-cell lymphoma, so image the small bowel and use capsule endoscopy. Small bowel adenocarcinoma can arise even in well-controlled disease.

13:05The next chapter covers the other diseases of the small bowel lining: non-celiac gluten sensitivity and the framework of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, FODMAPs, autoimmune enteropathy, Whipple disease, drug-induced enteropathy, checkpoint inhibitor enteritis and bacterial overgrowth, and tropical sprue.

13:30For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode two of two of chapter ten, and I'll see you in the next one.