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Coeliac disease (CD)

What is CD?

CD is a chronic systemic autoimmune disorder induced by gluten proteins present in wheat, barley, and rye. Gluten enteropathy is a systemic disease rather than merely an ailment of the alimentary tract.

How Prevalent is CD?

The prevalence of CD is in the range of 0.5% to 1.0%. There is increased prevalence in first degree relatives and patients with type 1 diabetes, iron deficiency anemia (IDA) and
osteoporosis.
It must be remembered that serologic and histologic markers of CD can develop after an initial negative screen in a genetically predisposed individual. Therefore, a one- time assessment or screen in these individuals may be insufficient.

Should you screen for CD?

Evidence today does not support mass screening of celiac disease because

  • Asymptomatic patients diagnosed at screening may lead to impaired quality of life because CD patients (esp. females) experience significantly more GI symptoms.
  • Poor dietary compliance in asymptomatic individuals
  • There is no evidence as yet to suggest that symptom-free CD patients run an increased risk of mortality, small intestinal lymphoma or other complications.
  • The prevention of osteoporosis seems to be the strongest indicator for widespread screening today. The clinical importance of the reduction of bone mineral density is the increased risk of fractures. The increased risk of fractures is modest and do not justify mass screening for CD.

Where should you consider screening?

Screening recommended Screening recommended when symptoms consistent with CD are present; Screening not recommended
  • Malabsorption, IDA
  • Infertility
  • Osteoporosis
  • Ataxia and polyneuropathy
  • Arthritis of unknown aetiology
  • Chronic liver disease of unknown aetiology
  • Suspicion of DH
  • IBS
  • Lactose intolerance.
  • Family h/o CD
  • Autoimmune thyroid disease
  • Sjogren’s syndrome
  • Addison’s disease
  • Autoimmune endocrinologic disease in general
  • Any chronic GI symptoms
  • General population
  • Acute or short term GI symptoms
  • Atopic symptoms
  • Type 1 diabetes

Discuss the pathogenesis of CD?

A Model of CD Pathogenesis:

  • Ingestion of gluten by a genetically susceptible individual with DQ2 or DQ8 alleles. Gluten is not fully digested because of its high proline content, and this gives rise to a number of large undigested gluten peptides.
  • The partially digested gluten peptides must cross the epithelial barrier to gain access to the subepithelial region, and the pathway involved here are as yet undetermined (ie, via the paracellular or, transepithelial routes or other routes)
  • In the lamina propria- gluten peptides encounter TTG and antigen-presenting cells (eg, macrophages, dendritic cells, B cells) that express DQ2 or DQ8. This binding of gluten peptides to DQ2 or DQ8 on antigen presenting cells is facilitated by autoantibodies against tissue transglutaminase.
  • The antigen presenting cells present some of these peptides to DQ2 or DQ8 restricted populations of CD4+ T cells, which become activated and release mediators that ultimately lead to tissue damage.

How Is CD Diagnosed?

  • Serology-The best available tests are the IgA antihuman tissue transglutaminase (TTG) and IgA endomysial antibody immunofluorescence (EMA) tests that appear to have equivalent diagnostic accuracy.
    • Sensitivity and specificity of these two tests exceed 95%. These tests may not be as accurate in the clinical setting.  Thus, in symptomatic individuals in whom there is strong clinical evidence for CD, a D2 biopsy should be considered even if the serologic test is negative.
    • Antigliadin antibody (AGA) tests are no longer routinely recommended because of their lower sensitivity and specificity.
    • There are no data to show that a combination of tests is better than a single test using either EMA IgA or TTG IgA.
    • The serologic tests for CD are IgA based and hence will be false negative in selective IgA deficiency.  IgG-based tests may be used in such cases; however, their accuracy remains to be determined. Thus, D2 biopsies may be best in symptomatic IgA deficient patients.
    • Serologic testing for CD in children < 5 years of age may be less reliable.
  • HLA typing- almost 100% of pts with CD have HLA DQ2 or DQ8. However, approximately 30% of the general population is also positive for the DQ2 haplotype. Thus HLA typing would not be very specific, but a negative test for both HLA DQ2 and DQ8 virtually excludes CD.
  • Histology-D2 biopsies are indicated in individuals with a positive CD antibody test, except those with biopsy-proven dermatitis herpetiformis. At least 4 samples should be obtained from D2 or beyond. The histologic abnormalities in the small-bowel mucosa usually are more pronounced proximally and therefore D2 biopsies should be representative.   Despite this practice, false negatives can occur. If the clinical suspicion is high, repeat duodenal biopsy examination or sampling of more distal small bowel should be considered.
    The Marsh classification has been adopted to describe the progression of the abnormalities in the coeliac mucosa.

    • Marsh type I lesion (infiltrative) comprises normal mucosal architecture with a lymphocytic infiltration of the villous epithelial layer.
    • Marsh II lesion (hyperplastic) exists if, in addition to a lymphocytosis, there is crypt hyperplasia shown by crypt branching and elongation, and increased mitotic activity. The villus height/crypt depth ratio often will become decreased below a normal value of 3–5.
    • Marsh III lesions (destructive) – villous atrophy.
    • Marsh IV lesion (hypoplastic) – flat atrophic mucosa. This abnormality may be related to RCD and the development of EATL.

CD has been traditionally diagnosed based on Marsh III lesions. The significance of Marsh I and II lesion is unclear. It is not yet known whether these individuals have the same adverse health risks as the traditional CD with villous atrophy. However, It is now clear that many individuals have gluten-sensitive inflammation without villous atrophy.     It should be remembered that an intraepithelial lymphocytosis is a nonspecific response to any adverse stimulus in the intestine and also can be found transiently in healthy individuals who do not have celiac disease.

What is gluten challenge?

Gluten challenge is generally needed in a patient who is already on a GFD despite not having been diagnosed with CD. Formal gluten challenge should comprise a daily intake of 10 g of gluten and this can be achieved by consuming 4 slices of white bread each day for a minimum of 4 weeks. If patients are particularly symptomatic it may be helpful to shorten this period to 2 weeks.

What are the Manifestations of Coeliac Disease?

CD is a multisystem disorder. The symptoms are sometimes triggered by events such as gastroenteritis, overseas travel, stress, or surgery.

  • Gastrointestinal manifestations-
    • Diarrhea, weight loss, failure to grow, vomiting, abdominal pain, bloating and distention, anorexia, and constipation. The presence of obesity does not exclude the diagnosis.
    • Iron and folate deficiency may occur with or without anemia.
    • Abdominal pain, bloating, and altered bowel habit may occur in the absence of malabsorption and this picture may be indistinguishable from IBS.
    • B12 deficiency is unusual as TI is normally unaffected. However, B12 deficiency occurs in 12% of CD patients.
  • Neurologic manifestations- CD has been associated with neurologic and psychiatric disorders including cerebellar ataxia, peripheral neuropathy, epilepsy, dementia, and depression. This association remains to be confirmed by larger epidemiologic studies.   It remains unclear whether gluten sensitivity contributes to the pathogenesis of these disorders or whether it represents an epiphenomenon. Studies of GFD in patients with CD & neurologic syndromes have shown variable results.
  • Other presentations are unexplained short stature, delayed puberty, infertility, recurrent fetal loss, osteoporosis, fatigue, recurrent aphthous stomatitis, elevated transaminases, and dental enamel hypoplasia.
  • Atypical presentations- increased serum amylase levels secondary to macroamylasemia, marked increase of ESR (>100) decreasing to normal on a GFD. Hyposplenism may lead to platelet counts greater than a million with or without Howell jolly bodies.
  • Dermatologic manifestations-
    • Dermatitis herpetiformis (DH)- DH is manifestation of CD. Clinically, 10%–20% of patients with DH have classic symptoms of malabsorption and another 20% are estimated to have atypical symptoms, but at least 60% of patients have “silent” CD.

How Is Dermatitis Herpetiformis diagnosed?

Patients with dermatitis herpetiformis demonstrate intensely pruritic papulovesicles and excoriations on the elbows, knees, buttocks, and scalp. It is extremely rare to have cases without characteristic involvement of one of these areas.
The presence of granular IgA in dermal papillary tips in perilesional skin is a sine qua non for the diagnosis of DH.

What other diseases are associated with CD?

Alopecia areata, psoriasis, and aphthous stomatitis. These diseases may clear on a GFD. Occasional patients with psoriasis have been reported to improve with gluten restriction.

What Is the Management of Dermatitis Herpetiformis?

  • GFD-DH respond in weeks to months to gluten restriction and recur with reinstitution of diet containing gluten.
  • Dapsone- DH clears rapidly on treatment with dapsone. The cutaneous disease, however, recurs rapidly if dapsone is discontinued. Dapsone suppresses the inflammation in the skin but has no influence on the intestinal abnormality. Many patients with DH choose to take dapsone chronically and not restrict gluten intake, despite knowing that gluten is the causative agent for their eruption.

What is silent and latent CD?

Silent CD refers to individuals who are asymptomatic but have a positive serologic test and villous atrophy on biopsy.
Latent celiac disease is defined by a positive serology but no villous atrophy on biopsy. These individuals are asymptomatic, but later may develop symptoms and/or histologic changes.

Discuss the management of CD?

  • Treatment for CD requires elimination of the storage proteins found in wheat, rye, and barley. Products labeled “gluten-free” tend to contain less than 200 ppm gluten (=200 mg gluten/1 kg).
  • Wheat starch (gluten protein have been removed) is a safe and well-tolerated addition to the GFD when the GFD is otherwise strict.   Most patients with coeliac disease tolerate these products well, although a minority cannot.
  • Oats are safe for most individuals with CD, but their practical inclusion in a gluten-free diet is limited by potential contamination with gluten during processing. Although some patients experience increased flatus and GI discomfort when consuming oats, this may be related to the increase in fiber while eating oats, rather than contamination.
  • Gluten-free products are often low in B vitamins, calcium, vitamin D, iron, zinc, magnesium, and fiber. Few gluten-free products are enriched or fortified, adding to the risk of nutrient deficiencies.  Also troubling is the increased incidence of obesity seen in persons with celiac disease following a gluten-free diet. This is due to a higher percentage of calories from fat and less from carbohydrates in a GFD. Thus, vitamin and mineral supplementation can be useful adjunct therapy to the GFD.
  • It is difficult to assure the safety of ingredients in non regulated herbal medications and similar nutritional supplements. Physicians may wish to write ‘’provide a gluten-free equivalent” on the prescriptions. It may also be useful to avoid generic substitutions, whose sources could change frequently.
  • Hyposplenism:  There is some degree of splenic atrophy in most patients with CD. This can be severe to cause peripheral blood changes in about 25%. Patients should therefore be considered for:
    • Vaccination against pneumococcus and haemophilus influenzae type b
    • Vaccination against influenza
    • Guidance about the increased risks attached to tropical infections eg malaria
  • Type 1 Diabetes and CD-
    • Many of the well-known complications of type 1 diabetes can be exacerbated by nutritional deficiencies.
    • Nocturnal hypoglycemia with seizures and recurrent, unexplained hypoglycemia with a reduction in insulin requirements should prompt testing for CD.
    • The GFD presents an additional challenge to the patient with diabetes. The diabetic patient with CD may see acute hyperglycemia with the initiation of a GFD and a steady rise in hemoglobin A1c. This can be due to intestinal healing and better absorption, as well as gluten-free substitutes, which may be corn, rice, or potato based, and have a higher glycemic index.
  • Osteoporosis- The British Society of Gastroenterology recommends a DEXA scan at diagnosis and a repeat scan;
    • At menopause for women
    • At the age of 55 years for men
    • At any age should a fragility fracture occur
    • Osteoporosis- T score below -2.5 (Osteoporosis defined as BMD >2.5 SD below mean for young adult). For those on steroids a T score below -1.5 has been recommended as a treatment threshold.
    • However, as BMD falls progressively with age, this might lead to treatment of most very elderly patients. To ration the treatment some recommend a threshold based on the Z score below -1.
    • Medications- a. Bisphosphonate or calcitonin b. HRT if female
    • Vitamin D deficiency should be sought and treated if found.
    • Low bone density associated with CD responds to a gluten-free diet with a gradual restoration of bone over 2 years.
    • For bisphosphonates and calcitonin measure BMD yearly
    • If BMD falls >4% per year in two successive years change to other drug
    • If no fall continue drug for at least three years — possibly long term as long as osteoporosis persists
    • Restart drug if, on stopping, yearly BMD falls >4%
    • For HRT check BMD after 10 years and continue HRT if osteoporosis persists
    • CD is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, & of the oesophagus. CD-associated adenocarcinoma presents with either acute (obstruction, hemorrhage) or chronic signs (anemia, abdominal pain, weight loss). In the majority of patients, complete surgical resection is possible.
    • NHL of Any Primary Site- There is some evidence to suggest the possibility of an increased risk for B-cell NHL in patients primarily affected with CD.
    • There may be an increased risk of primary liver cancer and melanoma.  In contrast, the risk of breast cancer may be reduced.
    • All-cause mortality among those with clinically diagnosed CD is about 2 times that of control populations.
    • children diagnosed before 10 years of age showed no increase in the risk of cancer
    • likewise, mortality for cancer was increased in all age groups but not in children who had started treatment before 2 years of age; and
    • the overall relative risk for cancer declined with the increasing length of follow-up evaluation.
    • CD patients should be followed up at 6-12 monthly intervals either by the gastroenterologist or the primary care physician.
    • It is important to review patients at times of stress, whether this be physical or emotional.  Pregnancy is a particularly important time which may lead to deterioration in symptoms, or asymptomatic nutritional deficiencies.   Patients who are contemplating conception should supplement their diet with folic acid as they are prone to folic acid deficiency.
    • Annual check should involve
      • Measure weight, height and body mass index
      • Assess symptoms.
      • Conduct investigations: FBC, red cell folate, serum ferritin, B12, Calcium, serum albumin and alkaline phosphatase.
      • Assess EMA or TTG to monitor significant dietary gluten ingestion.
    • Poor compliance or inadvertent gluten ingestion is the most common cause. TTG antibodies mostly return to normal within 2-3 months
    • Exclude other causes of diarrhoea with/without villous atrophy
      • Microscopic colitis
      • Concomitant or secondary lactase deficiency
      • Bacterial overgrowth
      • IBS
      • Coexisting pancreatic insufficiency
      • Other causes of villous atrophy- CVID, Eosinophilic enteritis, tropical sprue, Giardiasis, Crohn’s disease.
    • Refractory sprue
    • Ulcerative jejunitis and intestinal lymphoma

When to Treat?

  • Osteoporosis- T score below -2.5 (Osteoporosis defined as BMD >2.5 SD below mean for young adult). For those on steroids a T score below -1.5 has been recommended as a treatment threshold.
  • However, as BMD falls progressively with age, this might lead to treatment of most very elderly patients. To ration the treatment some recommend a threshold based on the Z score below -1.

What treatments are used?

  • Medications- a. Bisphosphonate or calcitonin b. HRT if female
  • Vitamin D deficiency should be sought and treated if found.
  • Low bone density associated with CD responds to a gluten-free diet with a gradual restoration of bone over 2 years.

What is the duration of such treatment?

  • For bisphosphonates and calcitonin measure BMD yearly
  • If BMD falls >4% per year in two successive years change to other drug
  • If no fall continue drug for at least three years — possibly long term as long as osteoporosis persists
  • Restart drug if, on stopping, yearly BMD falls >4%
  • For HRT check BMD after 10 years and continue HRT if osteoporosis persists

What are the complications of CD?

  • CD is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, & of the oesophagus. CD-associated adenocarcinoma presents with either acute (obstruction, hemorrhage) or chronic signs (anemia, abdominal pain, weight loss). In the majority of patients, complete surgical resection is possible.
  • NHL of Any Primary Site- There is some evidence to suggest the possibility of an increased risk for B-cell NHL in patients primarily affected with CD.
  • There may be an increased risk of primary liver cancer and melanoma. In contrast, the risk of breast cancer may be reduced.
  • All-cause mortality among those with clinically diagnosed CD is about 2 times that of control populations.

Does the GFD Protect Against Cancer Development?

Occurrence of cancers in patients on a GFD suggests that GFD may not be absolutely protective. However, many of these cases had previously been exposed to dietary gluten for a long time, usually for some decades, whereas the period on GFD was brief. Thus, the relatively short time on the diet might be insufficiently protective. Furthermore, it is impossible to completely avoid gluten.
The analysis of cancer incidence and mortality in the large Swedish cohort of CD patients clearly showed that

In summary, strict adherence to the GFD seems to be the only possibility of preventing a subset of rare but very aggressive forms of cancer.

Discuss the follow up patients with CD?

Coeliac serology can be used as an approximate marker of dietary compliance, although a decrease in titer does not correlate with histopathologic improvement.
In those whose antibody levels do not decrease within 12 months, dietary compliance should be checked and repeat biopsy examination should be performed as necessary by mutual consent.
Because of the false positivity of tTG and EMA with other autoimmune diseases, such as type 1 diabetes and autoimmune hepatitis, these antibodies may remain elevated in a certain subset of patients despite strict adherence to a GFD.

Discuss the causes of non response to GFD?

  • Poor compliance or inadvertent gluten ingestion is the most common cause. TTG antibodies mostly return to normal within 2-3 months
  • Exclude other causes of diarrhoea with/without villous atrophy
  1. Microscopic colitis
  2. Concomitant or secondary lactase deficiency
  3. Bacterial overgrowth
  4. IBS
  5. Coexisting pancreatic insufficiency
  6. Other causes of villous atrophy- CVID, Eosinophilic enteritis, tropical sprue, Giardiasis, Crohn’s disease.
  • Refractory sprue
  • Ulcerative jejunitis and intestinal lymphoma

Ref

  1. Gastroenterology supplement Volume 128, Issue 4, Supplement 1 (April 2005)

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