Coeliac disease

• 1. A Hidden Disease

  ›

  Coeliac disease can sit unrecognised for more than a decade after the first symptoms appear, and an estimated 70% of the people who have it never receive a diagnosis. North Americans spell it celiac. It is a chronic autoimmune disease, which means the immune system turns against the body it should protect. The trigger is gluten, a protein found in several common grains, and the main target is the small intestine. Yet the damage does not stay in the gut. Why can one protein disturb bones, liver, and fertility? Why do some people with the risk genes stay healthy while others do not? And what finally pointed a Dutch doctor toward wheat as the culprit?

  89495031

• 2. Symptoms Beyond the Gut

  ›

  Chronic diarrhoea that is pale, large in volume, and unusually foul-smelling is the textbook sign of classic coeliac disease. This form is most often seen in young children, though it can strike at any age. Weight loss and failure to thrive often come with it, because the damaged bowel cannot absorb nutrients properly. Abdominal pain, cramping, bloating, and mouth ulcers are also common. As the bowel is damaged further, lactose intolerance can develop.

  Adults more often have the non-classic form, where trouble shows up outside the intestine. Headaches, fatigue, brain fog, muscle pain, and joint pain are typical. Doctors call these extraintestinal manifestations, and they arise from malabsorption or from inflammation spreading through the body.

  Iron deficiency is one of the most frequent culprits, and it can lead to anaemia. Folate, zinc, vitamin D, and vitamin B12 can also run low. A shortage of vitamin D may cause secondary hyperparathyroidism, while poor absorption of fats can lead to hyperoxaluria and kidney stones. Bones thin as well, producing low bone density, called osteopenia, and osteoporosis.

  Left untreated, the disease can delay periods or puberty. It is associated with infertility and with pregnancy complications such as intra-uterine growth restriction and spontaneous abortion. Shortages of zinc, iron, folate, and selenium are thought to be behind these reproductive problems. The liver can be affected too. Raised transaminase levels with no other explanation are known as coeliac hepatitis.

  Many people with the disease report no symptoms at all, and are often found through screening programmes. Yet many who consider themselves symptom-free have simply grown used to chronically poor health. Once a gluten-free diet brings improvement, they can look back and recognise signs they had ignored. A further group has positive blood tests but no change in the small intestine, a state called potential coeliac disease.

  Rarer presentations include peripheral neuropathy, epilepsy, psoriasis, recurrent aphthous stomatitis, and pericardial effusion. Some, such as Lane-Hamilton syndrome, have an unclear relationship to the disease. What sets this whole-body reaction in motion begins with a pair of inherited genes.

  141516128

• 3. Genes and Gluten

  ›

  Gliadins and glutenins are the gluten proteins in wheat that provoke the reaction. Similar proteins in barley and rye, which belong to the tribe Triticeae, do the same. So do wheat relatives such as spelt, durum, and khorasan wheat, and the wheat hybrid triticale. Oats belong to a different tribe, Aveneae, and affect only a small number of people. Possible reasons include cross-contamination with gluten, differences between oat cultivars, or a separate intolerance to oats. Most people with the disease tolerate pure oats, although clinical guidelines disagree on whether they should eat them.

  Maize, millet, sorghum, teff, rice, and wild rice are safe. So are amaranth, quinoa, and buckwheat. Potatoes and bananas contain no gluten and trigger no symptoms.

  Almost everyone with coeliac disease carries a variant of the HLA-DQ gene called HLA-DQ2, or less commonly HLA-DQ8. The genes sit on the short arm of chromosome 6. Over 95% of patients have the DQ2 or DQ8 form of the protein. Yet about 40% of people without the disease carry one of these variants as well. The gene is therefore necessary but not sufficient, and other factors must join in.

  The reason these receptors matter is that they grip gliadin fragments more tightly than other versions do. That makes T lymphocytes more likely to switch on and start the autoimmune process. Most patients carry a two-gene arrangement called DQ2.5. People who inherit it from both parents are especially at risk and more prone to severe complications.

  The proteins responsible are mostly prolamins, storage proteins rich in proline and glutamine. They are named gliadin in wheat, hordein in barley, secalin in rye, and avenin in oats. Gut enzymes struggle to break them down. An enzyme called tissue transglutaminase then modifies the gluten fragments so the immune system reacts to them more strongly. The resulting new molecular shapes are believed to provoke autoantibodies against the enzyme itself.

  The T cell inflammation that follows wears away the structure of the small bowel lining, a change called villous atrophy. Absorption of nutrients suffers as a result. Other researchers propose that a shorter gluten fragment and the signalling molecule interleukin 15 can cause similar damage.

  Outside the body, environmental influences are suspected. Infections, geographic latitude, birth weight, antibiotic use, gut microbiota, and breastfeeding are all theorised to play a part. The timing of introducing gluten to infants does not seem to raise risk, though large early amounts may matter in those who are genetically predisposed.

  A puzzle remains. Untreated disease harms health and fertility, so these genes should have become rarer over time. The opposite happened, and they are most common where gluten-rich foods have been eaten for thousands of years. One suggestion is that HLA-DQ2 once helped protect against tooth decay.

  1830334528

• 4. Finding the Answer

  ›

  A blood test for tissue transglutaminase 2 antibodies of the IgA type, called TG2 IgA, has a sensitivity of 92.8% and a specificity of 97.9%. It is inexpensive and widely available, so it is the first choice. Results differ between laboratories because no formal standard exists. The test also performs less well in people whose intestines are only mildly damaged.

  Another test, for endomysial antibodies, is less sensitive but has a specificity near 100%. It is costly and hard to interpret, so it is reserved for borderline results. Because IgA deficiency is more common in coeliac patients, guidelines call for checking it too. In that case doctors turn to IgG-based tests. Older antigliadin and antireticulin tests are no longer recommended.

  A patient must still be eating gluten for any of this to work. Within months of cutting it out, the antibodies fall. Gluten may need to be reintroduced several weeks before testing. A formal gluten challenge means eating over 10 grams of gluten a day for three months, or until TG2 IgA turns positive. It is discouraged before the age of 6 and during pubertal growth. It is no longer needed when intestinal lesions fit the disease and the patient responds to a gluten-free diet.

  The second step is usually an upper endoscopy, with several biopsy samples taken from the duodenum or jejunum. Damage can be patchy, so a sample from healthy tissue produces a false negative. Most small intestines look normal during the procedure. Possible signs include scalloped folds, fissures, a mosaic pattern, and a nodular surface. Capsule endoscopy offers an alternative for people who cannot or will not undergo the standard procedure.

  Pathologists grade the biopsy using the Marsh classification, which Marsh described in 1992 and Oberhuber refined in 1999. It rests on three features: a high count of lymphocytes in the intestinal lining, elongated crypts, and shortened or absent villi. Other disorders can cause the same changes, so the findings alone do not prove coeliac disease. The list of look-alikes includes tropical sprue, Crohn's disease, giardiasis, and lymphoma.

  A 2020 guideline from the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition allows some children to skip the biopsy. They need symptoms, TTG IgA levels ten times higher than normal, and a positive endomysial antibody. Evidence is insufficient for adults.

  A related condition, non-coeliac gluten sensitivity, causes similar symptoms with a faster onset and offset. It is diagnosed by ruling out coeliac disease and wheat allergy.

  Screening everyone is contested. In 2017 the United States Preventive Services Task Force found insufficient evidence either way for people without symptoms. The British guidance from NICE instead lists triggers for testing, including persistent unexplained digestive symptoms, faltering growth, chronic fatigue, and unexplained iron, B12, or folate deficiency. Once the diagnosis stands, the only treatment on offer is a diet.

  5455526457

• 5. Living Gluten-Free

  ›

  Symptoms can improve within days of starting a gluten-free diet. The diet can also prevent further complications and normalise effects such as stunted growth. It means removing every food and drink that contains wheat, rye, barley, or their derivatives, for life.

  How little gluten is too much varies from person to person. Some people tolerate around 35 mg a day without intestinal damage. Others cannot manage more than 10 mg. International regulators require a product to contain less than 20 parts per million, about 6 mg per day, to carry a gluten-free label.

  Substitutes bring their own trouble. Rice, potato, corn, and tapioca starches are low in fibre and vitamins and higher in sugars and fats than their wheat equivalents. Treatment guidelines therefore recommend a dietitian, who can help patients spot hidden gluten and keep meals balanced. Gluten-free food has become cheaper over the past ten years but remains significantly more expensive. Its growing popularity among people without the disease has improved availability. It may also have made manufacturers less vigilant, and blurred public understanding of cross-contamination.

  Cross-contamination is a constant worry away from home. Eating out means disclosing a restriction and trusting the kitchen. Some patients develop a strained relationship with food, disordered eating, anxiety, or depression. A diagnosis can also carry stigma, which makes it harder to ask for help. Gluten in medications, cosmetics, and hygiene products is not covered by federal regulation, so mislabelling is possible even though the amounts are usually small.

  Medical follow-up is frequent at first, several visits a year, then once or twice a year. Doctors check symptoms, adherence, and complications. Tests may include a blood count, an iron panel, thyroid testing, liver enzymes, and vitamin D levels. A DEXA scan can check bone density. Guidelines also recommend pneumococcal vaccination because of the raised risk of pneumonia.

  Faith adds another layer. Christian Eucharist wafers made from wheat typically hold 2-5 mg of gliadin, and many patients change their religious practice because of them. United Methodist, Christian Reformed, Episcopal, Anglican, and Lutheran churches offer gluten-free alternatives, usually a rice-based cracker or bread. Catholic doctrine requires wheat bread for a valid Eucharist. Low-gluten hosts meet the rules, and as of 2017 the Vatican still disapproved of gluten-free bread for Communion.

  Passover presents a similar puzzle. The obligation to eat matzah, made from wheat, barley, spelt, oats, or rye, collides with the diet. Ashkenazi Jews also avoid rice during the festival, so many kosher-for-Passover products skip grains altogether and use potato starch instead.

  2126879193

• 6. When Diet Fails

  ›

  Around 20-40% of people with coeliac disease have non-responsive disease, meaning symptoms continue after 6 to 12 months without gluten. The most common cause is unintentional gluten intake. Other conditions can mimic it, including small intestinal bacterial overgrowth, giardiasis, FODMAP intolerance, microscopic colitis, pancreatic insufficiency, and Crohn's disease.

  About 1.5% of patients develop refractory coeliac disease. Malabsorption and villous atrophy persist after at least one year on the diet. It carries a high rate of illness and death, brings more severe symptoms, and is more common in older people. Specialists must confirm the original diagnosis and rule out other causes of intestinal damage.

  There are two subtypes. Type 1 shows tissue changes similar to untreated disease. Type 2 is marked by abnormal T cells that replace healthy lymphocytes in the small intestine. That raises the risk of enteropathy-associated T-cell lymphoma, severe malabsorption, and ulcerative jejunoileitis, and outcomes are poorer. Type 1 is treated with steroids, azathioprine, and budesonide. Type 2 often fails to respond to steroids, and azathioprine may increase the lymphoma risk. Proposed options include cladribine, cyclosporine, and stem cell transplants.

  People with the disease face a higher risk of cancer in the oropharynx, oesophagus, and small intestine. Small intestinal lymphoma is the most common, though still rare, and its prognosis is poor. Older age and refractory disease raise the risk. Overall mortality is also higher, but research disagrees on by how much.

  612485358

• 7. Clues From History

  ›

  Around 9500 BCE, people in the Fertile Crescent of Western Asia began cultivating grain, and coeliac disease probably did not exist before that. In the 2nd century, in the same region, Aretaeus of Cappadocia recorded a wasting illness with chronic diarrhoea. The word coeliac comes from the Greek koiliakos, meaning abdominal. His patient had stomach pain and was pale, feeble, and unable to work. Aretaeus blamed a lack of heat in the stomach, believed the illness struck the old and women, and excluded children. One cause he named was a "copious draught of cold water."

  A 15th-century prescription from Mamluk Cairo, attributed to Shams al-Din ibn al-'Afif, offers a rare medieval glimpse. He was the personal physician to Sultan Barsbay and director of the Qalawun hospital. His remedy combined herbs and plant waters for patients who could not tolerate wheat.

  Western medicine took notice in 1856, when Francis Adams presented a translation of Aretaeus to the Sydenham Society. In 1887 the paediatrician Samuel Gee gave the first modern description in children, in a lecture at the Hospital for Sick Children, Great Ormond Street, London. He wrote: "If the patient can be cured at all, it must be by means of diet." His own menu was off the mark. He forbade rice, sago, fruit, and vegetables, all of which are safe, and recommended raw meat and thin slices of toasted bread. One child was fed "a quart of the best Dutch mussels daily" but could not stand it for more than one season.

  In 1908 the American physician Christian Archibald Herter described what he called intestinal infantilism, noting stunted growth, which gave rise to the name Gee-Herter disease. In 1924 the paediatrician Sidney V. Haas reported benefits from a banana diet. That regimen stayed fashionable until the true cause was found.

  The breakthrough came from the Dutch paediatrician Willem Karel Dicke. During the Dutch famine of 1944-1945, flour was scarce, and Dicke noticed that deaths among children with the disease fell from over 35% to essentially zero. Once wheat returned, mortality rose back to earlier levels. A Birmingham team tied the problem to gluten in 1952. John W. Paulley described villous atrophy in 1954, from samples taken at surgery, which encouraged biopsies by endoscopy. The hereditary character was recognised in 1965, and in 1966 dermatitis herpetiformis was linked to gluten sensitivity.

  7071727678

• 8. Who Is Affected, What Is Next

  ›

  In most countries between 1 in 50 and 1 in 200 people have coeliac disease. It is less common where gluten-containing crops are rarely eaten. It is also less common in parts of east Asia and sub-Saharan Africa, where few people carry the HLA-DQ genes. Having a first-degree relative with the disease raises the risk, and second-degree relatives see a smaller rise.

  Diagnoses have climbed dramatically in recent decades thanks to greater awareness and wider blood testing. Undiagnosed cases are more common in poorer areas and in countries that do not routinely test at-risk people. Most people develop the disease before age 10, yet roughly 20 percent of patients are diagnosed after 60. Women are slightly more affected, although some of that gap may reflect practice, since men with digestive symptoms are less likely to be biopsied. Down syndrome, Turner syndrome, type 1 diabetes, and autoimmune thyroid disease, whether overactive or underactive, also raise the odds.

  Research is working on better tests. New blood tests aim to work in people who are not currently eating gluten, by measuring immune cells that react to it, such as CD4+ T cells and HLA-DQ-gluten tetramers. Food sensors such as the Nima sensor could let patients check meals for gluten. Kits that measure gluten in urine and waste might reveal whether someone is sticking to the diet.

  Treatment ideas are numerous. Scientists have explored altering wheat itself, through genetic manipulation or a chemical process called transamidation that changes gluten proteins so they no longer trigger the immune system. Chitosan and AGY gluten sequestering aim to keep gluten away from immune cells. Glutenases are enzymes taken with meals to break gluten down. Candidates include latiglutenase-ALV003, Aspergillus niger prolyl endoprotease, Kuma030-TAK-062, and endoprotease-40.

  Larazotide acetate, a peptide, tightens the junctions between intestinal cells so fewer gluten fragments slip through the gut lining. Other efforts target the T cells that react to gluten, hoping to switch off the intolerance itself.

  41106836100