Celiac Disease and Sprue Spectrum: Celiac Disease and Sprue Spectrum: Test and Treat

0:00Welcome to Board Pearls. This is episode one of two of the Celiac Disease and Sprue Spectrum chapter, in the Stomach and Small Bowel Disorders module. This episode follows celiac disease from the first clue to long-term follow-up. One woman carries it. Her case shows why her disease hid behind an irritable bowel label, why gluten injures only some people and how that shapes the tests, how the blood test must be done and the extra test always ordered with it, how to biopsy and what the biopsy can't show alone, when a genetic test helps, and how the gluten-free diet is run and checked. Episode two covers the patient who doesn't get better on the diet, and the complications, including lymphoma.

0:42Here's the patient. A twenty-eight-year-old woman has iron deficiency anemia that hasn't improved after six months of oral iron. Her periods are light, she eats meat, and a stool test for blood was negative. She has bloating and loose stools that her doctor called irritable bowel. Her mother has Hashimoto thyroiditis. She broke her wrist last year in a minor fall.

1:05Iron deficiency that doesn't respond to oral iron, with no blood loss to explain it, plus loose stools and a fracture from a minor fall, points to celiac disease, an immune enteropathy triggered by gluten. Her disease hid behind an irritable bowel label because adult celiac disease rarely looks like the textbook. The classic picture of steatorrhea, weight loss, and distension is now the minority. About forty percent of adults present with symptoms that look like irritable bowel syndrome, IBS: bloating, pain, alternating bowel habits, and urgency. So celiac serology is checked before an irritable bowel diagnosis is accepted.

1:43Her iron deficiency is the second most common presentation, in about one in five adults, especially iron deficiency that doesn't respond to oral iron. The reason is lost absorptive surface in the duodenum, where iron is absorbed, plus a small amount of occult blood loss from the mucosa. A young woman with iron deficiency that fails oral iron, with no menstrual or gastrointestinal, GI, blood loss to explain it, is the textbook celiac vignette.

2:10Her fracture fits another common single-organ presentation. Osteoporosis, or a vertebral fracture in a young or middle-aged adult, comes from poor calcium and vitamin D absorption with secondary hyperparathyroidism. Reproductive problems are recognized too: infertility in either sex, recurrent miscarriage, late menarche, or early menopause.

2:33Other single organs can be the only clue. Unexplained transaminases, typically sixty to two hundred, usually resolve on the diet, while persistent elevation on the diet prompts a workup for autoimmune hepatitis or primary biliary cholangitis. Neurologic features include peripheral neuropathy, epilepsy, headache, and gluten ataxia, a cerebellar syndrome with anti-gliadin and anti-transglutaminase six antibodies. Dental enamel defects, mouth ulcers, and a small, poorly functioning spleen, with a high platelet count and Howell-Jolly bodies on the smear, complete the list.

3:04She has three clues: iron deficiency unresponsive to iron, IBS-type symptoms, and a fracture after a minor fall. Her family history adds a fourth, because celiac disease clusters with other autoimmune conditions. They're type one diabetes, autoimmune thyroid disease, primary biliary cholangitis and autoimmune hepatitis, Sjogren disease, and selective immunoglobulin A, IgA, deficiency, as well as Down and Turner syndromes. Her mother's Hashimoto thyroiditis fits that pattern.

3:36The tests for celiac disease come straight from its mechanism, which also explains why gluten injures only some people. Gluten is the family of storage proteins in wheat, rye, and barley. It's rich in proline, which makes it resistant to digestion, so long gluten peptides survive intact. They cross the lining into the lamina propria, leaking between cells through tight junctions loosened by zonulin and carried through microfold cells.

4:01There, the enzyme tissue transglutaminase modifies them, converting certain glutamines to glutamate. That single charge change lets the peptides bind tightly to two human leukocyte antigen, HLA, molecules, HLA-DQ2 or HLA-DQ8, on antigen-presenting cells. Those cells activate gluten-specific CD4, cluster of differentiation four, T cells, which secrete interferon gamma and interleukin twenty-one and drive inflammation.

4:30The damage itself comes from a second signal. Interleukin fifteen, made by stressed surface cells, macrophages, and dendritic cells, turns the lymphocytes within the lining into killers that destroy the surface cells and escape the control of regulatory T cells. The villi flatten, and the crypts deepen to compensate, which is villous atrophy. That same interleukin fifteen drive lets abnormal lymphocyte clones emerge in long-standing disease, which is how refractory disease and lymphoma arise later.

5:00Two parts of that mechanism become her tests. B cells in the same tissue make antibodies against the enzyme itself, tissue transglutaminase, which is why that antibody is the diagnostic blood test. And the HLA requirement explains the genetic test. About ninety to ninety-five percent of patients carry DQ2, and most of the rest carry DQ8, and without one, celiac disease is essentially impossible. But thirty to forty percent of the population carries one, and only about one percent develops the disease. So a negative HLA test essentially excludes celiac disease, while a positive one only shows susceptibility.

5:40That one percent is the prevalence in the United States and Europe, and her demographics fit it. The disease is more common in Northern Europe, Scandinavia, Spain, and Finland, and in Punjab in northwest India, and rare in people of purely sub-Saharan African or Southeast Asian ancestry. Women outnumber men about one and a half to one, most of all in young adults like her. The age pattern peaks in the first two years of life and again in middle age, the average adult is diagnosed around forty-five, and the diagnosis often comes ten to eleven years after symptoms begin. First-degree relatives have about a five to ten percent risk, which is why family members are screened.

6:20Testing her has one rule first: she must still be eating gluten. A gluten-free diet lowers the antibodies and heals the bowel, so both the blood test and the biopsy become falsely negative. A patient who has already gone gluten-free on her own has two options. One is a gluten challenge, about ten grams of gluten a day, roughly three slices of wheat bread, for one to three months before testing. The other is HLA testing, which can exclude the disease if it's negative.

6:48Her first blood test, as for anyone over age two, is tissue transglutaminase IgA, always ordered with a total IgA level. The antibody test has about ninety-five to ninety-eight percent sensitivity and specificity, which makes it the most cost-effective single test. The total IgA is essential because selective IgA deficiency affects two to three percent of celiac patients, ten to fifteen times the background rate, and an IgA-deficient patient will have a falsely negative IgA antibody.

7:18A low total IgA changes the test. If total IgA is low, IgG-based tests are used instead, with immunoglobulin G, IgG, deamidated gliadin peptide preferred and IgG tissue transglutaminase acceptable. Endomysial antibody IgA targets the same enzyme and is highly specific, but it's an operator-dependent immunofluorescence test that's slower and more expensive. So it's used to confirm a markedly high tissue transglutaminase when biopsy isn't done. Old anti-gliadin antibodies aren't specific enough and aren't recommended.

7:55Her tissue transglutaminase IgA is twelve times the upper limit of normal, with a normal total IgA.

8:03A positive antibody goes to biopsy, which has its own protocol and its own limits. At endoscopy, at least four biopsies are taken from the distal duodenum plus one or two from the duodenal bulb, at the nine and twelve o'clock positions. The bulb biopsies matter because in about ten percent of patients the damage is confined to the bulb, and a protocol that skips it misses them. The endoscopist may see scalloped or flattened folds, a mosaic pattern, or visible submucosal vessels, and water immersion can bring out subtle changes, but appearance alone can't make or exclude the diagnosis.

8:36The pathologist grades the biopsies by the Marsh classification. Marsh zero is normal mucosa. Marsh one is increased intraepithelial lymphocytes, more than twenty-five per hundred surface cells in the duodenum or forty in the jejunum, with normal villi. Marsh two adds crypt hyperplasia. Marsh three adds villous atrophy, graded three A for partial, three B for subtotal, and three C for total, a flat mucosa.

9:05The biopsy can't make the diagnosis on its own, because both of its findings have other causes. Raised lymphocytes alone are nonspecific, occurring with H. pylori, nonsteroidal anti-inflammatory drugs, NSAIDs, bacterial overgrowth, post-infectious enteritis, inflammatory bowel disease, and other immune diseases. Villous atrophy has other causes too, including olmesartan, mycophenolate, NSAIDs, tropical sprue, autoimmune enteropathy, common variable immunodeficiency, Giardia, Whipple disease, eosinophilic gastroenteritis, lymphoma, and graft-versus-host disease. That's why celiac disease is diagnosed from serology and biopsy together.

9:48Her biopsies show subtotal villous atrophy, Marsh three B, with many intraepithelial lymphocytes. With her serology, she has celiac disease.

9:58Her antibody was high enough that the biopsy might have been skippable, but only conditionally. In adults, a compatible clinical picture, a tissue transglutaminase IgA more than ten times normal, and a positive endomysial antibody on a second blood sample are nearly always right. But that's a conditional option for adults who can't or won't have endoscopy, not the default. International guidelines still require biopsy in adults, while European pediatric practice accepts the no-biopsy approach in children who meet the same criteria. Biopsy remains the standard adult confirmation.

10:32She didn't need HLA testing, and it isn't part of the routine workup, because a positive result says so little. It has four uses. It excludes celiac disease in someone already gluten-free who won't do a challenge. It resolves discordant results, such as positive serology with a normal biopsy, or the reverse. It screens high-risk children. And it settles ambiguous cases.

10:55Her disease was symptomatic, but three other forms are defined by what's missing, and each has its own rules. Silent celiac disease is positive serology and villous atrophy without symptoms, usually found by screening a high-risk group. It's still treated, because the long-term complications, osteoporosis, lymphoma, and small bowel adenocarcinoma, develop regardless of symptoms. Potential celiac disease is positive serology with normal villi and only raised lymphocytes, and whether to treat depends on how it evolves.

11:28Seronegative celiac disease, about five percent of biopsy-proven cases, is villous atrophy with negative antibodies. It's diagnosed by histology plus DQ2 or DQ8 plus a response to the diet, after excluding mimics, especially olmesartan.

11:46One skin disease is celiac disease by definition, and it's diagnosed from the skin. A patient with an intensely itchy rash of small blisters on the extensor surfaces, elbows, knees, buttocks, scalp, neck, and trunk, often scratched raw by the time it's seen, has dermatitis herpetiformis. It's caused by IgA against epidermal transglutaminase, transglutaminase three, distinct from the intestinal enzyme. A biopsy of the skin next to a lesion shows granular IgA in the dermal papillae on immunofluorescence, which is pathognomonic.

12:21Its treatment covers both organs. Every patient with dermatitis herpetiformis has celiac disease, with or without gut symptoms, and first-degree relatives should be screened. Treatment is the gluten-free diet, which treats both the skin and the gut, plus dapsone to control the itch while the diet takes effect. Dapsone treats the rash but not the bowel. It needs glucose-6-phosphate dehydrogenase, G6PD, testing first, because it causes hemolysis in G6PD deficiency, and liver monitoring, because it can injure the liver.

12:55With the diagnosis made, the damage she already has is assessed. That means a blood count, iron studies, B12, folate, vitamin D, calcium, magnesium, copper, zinc, liver tests, and thyroid function, plus a baseline bone density scan. Her vitamin D is low, and her dual-energy x-ray absorptiometry, DEXA, scan shows osteopenia, which explains the wrist.

13:29Her treatment is entirely the gluten-free diet, strict and lifelong. It excludes wheat, barley, and rye and anything made from them, including spelt, einkorn, emmer, triticale, and kamut. It allows rice, corn, potato, quinoa, amaranth, millet, sorghum, tapioca, teff, wild rice, and buckwheat, which despite its name isn't wheat.

13:55The biggest practical problem is cross-contamination, from shared production lines, cooking surfaces, and hidden ingredients. So every patient sees a dietitian experienced in celiac disease at diagnosis. Foods labeled gluten-free must contain under twenty parts per million, which allows healing in most patients. Handheld gluten detectors aren't reliable enough for clinical decisions.

14:19Oats are a special case. Pure oats are tolerated by most patients, because their protein differs structurally from wheat gluten. The problems are contamination, since oats are often grown or processed alongside wheat, and a small subset who react to oat protein itself. So oats should be certified gluten-free and introduced carefully, with monitoring.

14:39Two measures beyond the diet protect her from the disease's systemic effects. She gets pneumococcal vaccination, because some patients have a poorly functioning spleen, with splenic atrophy, a high platelet count, and Howell-Jolly bodies, and a higher risk of infection with encapsulated organisms. And her bones are protected: calcium and vitamin D are replaced, and the DEXA is repeated every three years if it's abnormal, or every five if it's normal.

15:05Her other deficiencies are replaced as the bowel heals. Iron, B12, and folate are replaced as needed, and iron absorption improves as the duodenum heals. Copper and zinc are checked after prolonged untreated disease.

15:20Follow-up checks that the diet is working. Tissue transglutaminase IgA should fall substantially by six months and normalize by twelve in most patients, though high starting levels can take longer. Visits every three to six months in the first year, then every one to two years, check symptoms, adherence, serology, and labs.

15:40The antibody and the biopsy answer different questions. A positive antibody after twelve months almost always means ongoing gluten exposure, intentional or accidental, so the first step is a dietitian review. But a normal antibody doesn't prove the bowel has healed, because serology and histology can disagree. A follow-up biopsy after about two years on the diet confirms mucosal healing in adults, sooner if symptoms persist or serology doesn't normalize. Healing is linked to fewer long-term complications, including lymphoma and small bowel adenocarcinoma.

16:14No drug treats celiac disease, so the diet stays the whole treatment. Several drugs have been tested, including a tight-junction stabilizer, gluten-degrading enzymes, an anti-interleukin fifteen antibody, and a tolerance vaccine, and none has been approved.

16:31Her antibody is normal at twelve months, her iron recovers on oral iron as her duodenum heals, and her biopsy at two years shows healed villi.

16:40Here are the traps the boards set in this patient. Testing doesn't happen after the patient has gone gluten-free. The total IgA isn't skipped. Too few biopsies, or none from the bulb, miss the disease. Raised lymphocytes alone don't make the diagnosis. HLA testing excludes celiac disease but doesn't diagnose it. And an irritable bowel label isn't accepted without serology.

17:04The treatment traps close the list. Dapsone isn't started without G6PD testing. Pneumococcal vaccination and bone density aren't forgotten. Persistent antibodies aren't blamed on anything but gluten before a dietitian review. And normal serology doesn't mean a healed bowel.

17:21So, start to finish. Gluten peptides, modified by tissue transglutaminase, bind DQ2 or DQ8 and drive T cells that flatten the villi. A negative HLA test excludes the disease, and a positive one doesn't confirm it.

17:36Adult celiac disease usually looks like something else: IBS-type symptoms, iron deficiency that doesn't respond to iron, early osteoporosis, infertility, or abnormal liver tests. Test on a gluten-containing diet with tissue transglutaminase IgA and total IgA. Confirm with four distal duodenal biopsies plus the bulb, and read them knowing that lymphocytes and atrophy have other causes. Dermatitis herpetiformis always means celiac disease.

18:04Treat with a strict lifelong gluten-free diet guided by a dietitian, vaccinate against pneumococcus, and protect bone. Monitor serology to normal by twelve months and the mucosa by biopsy at about two years.

18:17Episode two is the patient who still has symptoms on the diet: the order in which to look for the cause, refractory celiac disease and its two types, and the lymphoma and other cancers that can follow.

18:28For 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 one of two of chapter ten, and I'll see you in the next one.