MJA
MJA InSight
MJA Careers
Clinical update

Coeliac disease: the great imitator

John M Duggan
Med J Aust 2004; 180 (10): 524-526.
Abstract
  • Coeliac disease (CD) is caused by a complex immunological response provoked by grain protein in susceptible people.

  • The majority of people with CD are symptom-free adults; the remainder are prone to a bewildering variety of signs and symptoms, ranging from infertility to type 1 diabetes.

  • Many patients with undiagnosed CD spend years seeking help for complaints such as chronic tiredness or mild abdominal symptoms.

  • In primary care, an appropriate target group to test for CD is people with anaemia (especially women), chronic tiredness, non-specific abdominal symptoms (including so-called “irritable bowel syndrome”), or a family history of CD.

  • The response to an appropriate gluten-free diet is often life-transforming for symptomatic patients.

  • Positive serological tests for CD require confirmation by duodenal biopsy and, if confirmed, referral to a dietitian and a coeliac society, followed by a life-long gluten-free diet.

Know syphilis in all its manifestations and all other things clinical will be added unto you.1

When the supreme clinician William Osler wrote this, he was drawing attention to the ubiquity of syphilis and the remarkable range of its late-stage manifestations, today virtually unknown. However, I argue that its place has been taken by coeliac disease (CD), another great imitator. As a diagnostic challenge, CD is the “syphilis” of the 21st century.

Western civilisation owes much of its foundation to a strange molecular rearrangement of the chromosomes of wild grasses in the Middle East to produce a high-protein, high-yielding grain — wheat — with six sets of chromosomes. This enabled the nomads to settle down with some assurance of a regular food supply and time to think and develop skills such as writing.

This progress, however, came at a price. Gliadin, the principal wheat protein, presented to sensitised T cells in conjunction with HLA-DQ2 or HLA-DQ8 antigen, leads to the production of cytokines. The cytokines cause tissue damage within the mucosa and activate plasma cells to produce antibodies to gliadin, tissue transglutaminase and endomysium. Wheat, rye, barley and, to a minor extent, oats have progressively lesser amounts of the toxic amino acid sequence. Why only a small proportion of the population who are bearers of HLA-DQ2 and HLA-DQ8 produce these changes is unknown, as is why cigarette smoking reduces the risk of CD by 80%.2 However, what we are progressively learning is that the ill effects of the molecular events extend far beyond the small-bowel mucosa. For every classical thin, pale, pot-bellied patient with steatorrhoea, there are many with few or no symptoms, amounting in most North American and European societies to 0.5% to 1.0% of the population, particularly those of northern European ancestry.3

It is becoming evident that a host of disorders in many systems are aetiologically related to the presence of CD, often manifesting themselves in the context of an inapparent coeliac state (Box 1). For some, such as fatty liver “transaminitis” or hepatitis, the link is clear. Our research (as yet unpublished) shows that about 40% of both children and adults with this disorder (who typically have laboratory and histological evidence of CD but few clinical signs) have liver abnormalities that resolve within a few months on an appropriate diet.

Dermatitis herpetiformis is another condition that is clearly linked to CD. Most, if not all, cases of this form of dermatitis are related to gluten intolerance, although the duodenal changes may only manifest themselves after prolonged high intake of gluten.34 With a gluten-free diet, the condition resolves and the intense itchiness subsides.

Another association is with type 1 diabetes. The prevalence of CD in people with type 1 diabetes is about 3 to 8%,4 while the prevalence of type 1 diabetes in people with CD is about 5%.32 However, there are no data on whether patients with diabetes and CD experience improvement in their diabetes symptoms in response to a gluten-free diet.

Another group of associations is exemplified by the anaemias — essentially a complication of malabsorption, particularly of iron and folate. These conditions respond fully to nutrient replacement.

However, the largest, possibly most important and least understood group of diseases that appear to have links with CD are those with a statistical association, such as epilepsy,32 the neuropathies32 and myelopathies,10 the ataxias,12 and male and female infertility.16,17 With these conditions, the story is only beginning to unfold, and responses to diet are less evident.

Such associations are only likely to be detected, and their nature and course unravelled, if physicians have a much lower threshold for suspecting CD behind many different clinical syndromes (Box 2). By performing simple and relatively inexpensive laboratory tests — such as tests for transglutaminase antibody (sensitivity, 93%; specificity, 99%) and the endomysial antibody (sensitivity, 85%–98%; specificity, 97%–100%) — followed by endoscopic duodenal biopsy in antibody-positive patients, the disease is readily diagnosed.

Possibly the clearest data on a feasible approach to the disease are given in a study in nine general practices in the United Kingdom.36 The study found 30 patients with CD in a target group of 1000 adults with major complaints of feeling “tired all the time”, having abdominal symptoms or having a positive family history of CD. While universal screening for CD may not be feasible, or indeed appropriate, the study shows that screening patients with one or more of these symptoms may be a practicable alternative for discovering more cases of undiagnosed CD. However, there are a number of caveats. While the patient with long-term lethargy and folate or iron deficiency in the presence of a reasonable diet is likely to undergo life-transforming change on a gluten-free (GF) diet with appropriate supplementation, the imposition of a GF diet for the chance finding of CD in an effectively symptom-free patient may be a disservice. This is especially so for many of the associated disorders such as type 1 diabetes, for which we at present lack evidence of benefit of instituting a GF diet. Moreover, having found elevated transaminase and glutaminase antibody levels, the practitioner is obliged to seek an endoscopy and duodenal biopsy and referral to a coeliac society if CD is indicated. Given that GF diets are complex, lifelong, expensive and socially disruptive, they must always be preceded by histological proof from a biopsy. Nevertheless, the potential benefits for some patients may be enormous.

In the Australian context, an appropriate strategy is to request testing for endomysial and transglutaminase antibodies, ensuring that the laboratory tests for IgG antibodies in patients who have IgA deficiency, which is common in patients with CD.37 An appropriate group of patients to target would be those who have the type of symptoms described above in the UK study.36

In summary, there can be little doubt that the transglutaminase/endomysial antibody assay should be part and parcel of the diagnostic armamentarium of every physician, given that CD can manifest as a disturbance of function of virtually any body system. A priori, there must be many other associations yet to be discovered.

1: Clinical disorders associated with coeliac disease

Gastrointestinal

Liver disease “transaminitis”, hepatitis, fatty liver, primary biliary cirrhosis, cirrhosis*

Recurrent aphthous mouth ulcers4

Irritable bowel syndrome5

Lymphocytic gastritis6

Ulcerative jejunitis7

Reflux oesophagitis8

Adenocarcinoma of small bowel9

Neurological

Peripheral neuropathy10

Epilepsy11

Ataxia12

Myelopathy10

Psychiatric

Depression13

Schizophrenia14

Endocrine

Type 1 diabetes15

Infertility in men and women16,17

Recurrent abortion18

Thyroid disorders19

Addison’s disease19

Renal

IgA nephropathy20

Haemopoietic

Anaemia (iron, folate and vitamin B12 deficiency)21

Coagulation disorders from vitamin K deficiency21

IgA deficiency4

Hyposplenism20

T-cell lymphoma20

Locomotor

Osteopenia22

Arthralgia/arthritis23,24

Dermatological

Dermatitis herpetiformis25

Psoriasis26

Brown pigmentation of face and buccal mucosa27

Dental

Defects in tooth enamel28

Genetic

Down syndrome29

Cardiovascular

Cardiomyopathy30

Other

Alopecia areata31

Sjögren’s syndrome32

Finger clubbing27

Pharyngeal and oesophageal carcinoma33


* Duggan JM and Duggan AE (unpublished observations).

2: Coeliac disease: mode of presentation, and prevalence of the various symptoms/findings among presenting patients35,36

Mode of presentation

Proportion of patients with this primary presentation

Prevalence of symptom/finding


Anaemia

10%–18%

12%–22%

Feeling “tired all the time”

20%

58%

Malabsorption/bowel symptoms

43%

60%

Coeliac disease in first-degree relative(s)

13%

5%–10%

Symptoms in childhood

na

50%

Incidental finding at endoscopy

8%

na


na = not applicable.

John M Duggan, MD, FRACP, FRCP, Physician
Princeton Medical Centre, Hamilton, NSW.
Competing interests: 

None identified.

Reference Text: 
Bean WB. Sir William Osler: aphorisms, 133. In: Silverman MB, Murray TJ, Bryant CS, editors. The quotable Osler. Philadelphia: American College of Physicians, American Society of Internal Medicine, 2002: 145.
Reference Order: 
1
PubMed ID: 
Reference Text: 
Suman S, Williams EJ, Thomas PN, et al. Is the risk of adult coeliac disease causally related to cigarette exposure? Eur J Gastroenterol Hepatol 2003; 15: 995-1000.
Reference Order: 
2
PubMed ID: 
12923372
Reference Text: 
Fasano A, Berti I, Gerarduzzi T. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States. Arch Intern Med 2003; 163: 286-292.
Reference Order: 
3
PubMed ID: 
12578508
Reference Text: 
Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med 2002; 346: 180-187.
Reference Order: 
4
PubMed ID: 
11796853
Reference Text: 
Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001; 358: 1504-1508.
Reference Order: 
5
PubMed ID: 
11705563
Reference Text: 
Vogelsang H, Oberhuber G, Wyatt J. Lymphocytic gastritis and gastric permeability in patients with celiac disease. Gastroenterology 1996; 111: 73-77.
Reference Order: 
6
PubMed ID: 
8698227
Reference Text: 
Mills PR, Brown IL, Wilkinson G. Idiopathic chronic ulcerative enteritis. QJM 1980; 49: 133-149.
Reference Order: 
7
PubMed ID: 
7433632
Reference Text: 
Cuomo A, Romano M, Rocco A, et al. Reflux oesophagitis in adult coeliac disease: beneficial effects of a gluten free diet. Gut 2003; 52: 514-517.
Reference Order: 
8
PubMed ID: 
12631661
Reference Text: 
Holmes GK, Prior P, Lane MR, et al. Malignancy in coeliac disease – effect of a gluten free diet. Gut 1989; 30: 333-338.
Reference Order: 
9
PubMed ID: 
2707633
Reference Text: 
Hadjivassiliou M, Gibson A, Davies-Jones GA, et al. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369-371.
Reference Order: 
10
PubMed ID: 
8598704
Reference Text: 
Cronin CC, Jackson LM, Feighery C, et al. Coeliac disease and epilepsy. QJM 1998; 91: 303-308.
Reference Order: 
11
PubMed ID: 
9666954
Reference Text: 
Hadjivassiliou M, Grunewald RI, Sharrack B, et al. Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain 2003; 126: 685-691.
Reference Order: 
12
PubMed ID: 
12566288
Reference Text: 
Holmes GKT. Non-malignant complications of coeliac disease. Acta Paediatr Suppl 1996; 412: 68-75.
Reference Order: 
13
PubMed ID: 
8783765
Reference Text: 
De Sanctis A, Addolorato G, Romito A, et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med 1997; 242: 421-423.
Reference Order: 
14
PubMed ID: 
9408073
Reference Text: 
Sjoberg K, Eriksson KF, Bredberg A, et al. Screening for coeliac disease in adult insulin-dependent diabetes mellitus. J Intern Med 1998; 243: 133-140.
Reference Order: 
15
PubMed ID: 
9566642
Reference Text: 
Sher K, Mayberry J. Female fertility, obstetric and gynaecological history in coeliac disease: a case control study. Gastroenterology 1994; 55: 243-246.
Reference Order: 
16
PubMed ID: 
Reference Text: 
Sher KS, Jayanthi V, Probert CSJ, et al. Infertility, obstetric and gynaecological problems in coeliac disease. Dig Dis 1994; 12: 186-190.
Reference Order: 
17
PubMed ID: 
7988065
Reference Text: 
Gasparrini A, Torre ES, Trivellini C, et al. Recurrent spontaneous abortion and intrauterine fetal growth retardation as symptoms of coeliac disease. Lancet 2000; 356: 399-400.
Reference Order: 
18
PubMed ID: 
10972376
Reference Text: 
Collin P, Maki M. Associated disorders in coeliac disease: clinical aspects. Scand J Gastroenterol 1994; 29: 769-775.
Reference Order: 
19
PubMed ID: 
7824853
Reference Text: 
Parnell NDJ, Ciclitra PJ. Review article: coeliac disease and its management. Aliment Pharmacol Ther 1999; 13: 1-13.
Reference Order: 
20
PubMed ID: 
9892874
Reference Text: 
Bodé S, Gudmand-Hoyer E. Symptoms and haematological features in consecutive adult coeliac patients. Scand J Gastroenterol 1996; 3: 54-60.
Reference Order: 
21
PubMed ID: 
Reference Text: 
Lindh E, Ljunghall S, Larsson K, Lavo B. Screening for antibodies against gliadin in patients with osteoporosis. J Intern Med 1992; 231: 403-406.
Reference Order: 
22
PubMed ID: 
1588266
Reference Text: 
Lubrano E, Ciacci C, Ames PR, et al. The arthritis of coeliac disease: prevalence and pattern in 200 patients. Br J Rheumatol 1996; 35: 1314-1318.
Reference Order: 
23
PubMed ID: 
9010064
Reference Text: 
Usai P. Adult coeliac disease is frequently associated with sacroiliitis. Dig Dis Sci 1995; 40: 1906-1908.
Reference Order: 
24
PubMed ID: 
7555441
Reference Text: 
Trier JS. Celiac sprue. N Engl J Med 1991; 325: 1709-1719.
Reference Order: 
25
PubMed ID: 
1944472
Reference Text: 
Ojetti V, Sanchez JA, Guerriero C, et al. High prevalence of celiac disease in psoriasis [abstract]. Gastroenterology 2003; Suppl 1: A656.
Reference Order: 
26
PubMed ID: 
Reference Text: 
Spiro HM. Celiac disease. In: Spiro HM. Clinical gastroenterology. Toronto: MacMillan, 1970.
Reference Order: 
27
PubMed ID: 
Reference Text: 
Maki M, Collin P. Coeliac disease. Lancet 1997; 349: 1755-1759.
Reference Order: 
28
PubMed ID: 
9193393
Reference Text: 
Gale L, Wimalaratna H, Brotodiharjo A, Duggan JM. Down syndrome is strongly associated with coeliac disease. Gut 1997; 40: 492-496.
Reference Order: 
29
PubMed ID: 
9176077
Reference Text: 
Fonager K, Sorensen HT, Norgard B, Thulstrup AM. Cardiomyopathy in Danish patients with coeliac disease. Lancet 1999; 354: 1561.
Reference Order: 
30
PubMed ID: 
10551530
Reference Text: 
Corazza GR, Andreani ML, Venuro N, et al. Celiac disease and alopecia areata: report of a new association. Gastroenterology 1995; 109: 1333-1337.
Reference Order: 
31
PubMed ID: 
7557104
Reference Text: 
Collin P, Reunala T, Pukkala E, et al. Coeliac disease – associated disorders and survival. Gut 1994; 35: 1215-1218.
Reference Order: 
32
PubMed ID: 
7959226
Reference Text: 
Fasano A. Celiac disease — how to handle a clinical chameleon. N Engl J Med 2003; 348: 2568-2570.
Reference Order: 
33
PubMed ID: 
12815143
Reference Text: 
Weinstein WM. Latent celiac sprue. Gastroenterology 1974; 66: 489-493.
Reference Order: 
34
PubMed ID: 
4821074
Reference Text: 
Lo W, Sano K, Lebwohl B, et al. Changing presentation of adult celiac disease. Dig Dis Sci 2003; 48: 395-398.
Reference Order: 
35
PubMed ID: 
12643621
Reference Text: 
Hin H, Bird G, Fisher P, et al. Coeliac disease in primary care: case funding study. BMJ 1999; 318: 164-167.
Reference Order: 
36
PubMed ID: 
9888912
Reference Text: 
Green PHR, Jabri B. Coeliac disease. Lancet 2003; 362: 383-391.
Reference Order: 
37
PubMed ID: 
12907013