Coeliac disease
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.a3058 (Published 19 February 2009) Cite this as: BMJ 2009;338:a3058
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Roger Jones and Sarah Sleet argue powerfully that coeliac disease is
heavily under-diagnosed, although it affects a remarkable 1% of the
population.1 Further to the points mentioned, I would suggest that two
additional factors contribute to this situation – the nature of
serological screening tests used and patient selection for testing.
The authors correctly point out the high specificity and sensitivity
of the IgA anti-tissue transglutaminase (IgA-TTG) ELISA, which must sound
reassuring to doctors who request this test. Certainly, the negative
predictive value of this assay is uniformly high, making it very useful to
exclude coeliac disease. However, there is emerging evidence that the
positive predictive value of the IgA-TTG ELISA test for coeliac disease in
the community is commonly less than 50%. In other words, false positive
tests are frequent when this test is applied in real life, as opposed to
scientific study. My colleagues and I found that this was the case in a
local audit of test performance 2 and noted that at least three other
centres have published a similar experience.3-5 This calls into question
the need to secondarily screen all IgA-TTG positive samples with the more
stringent IgA anti-endomysium antibody (IgA-EMA) test. The advantage of
this approach is that positive predictive value is higher should both
tests prove abnormal.4,5 However, this raises the thorny question of what
to do with those who are IgA-TTG positive and IgA-EMA negative.
The second issue is when to consider coeliac disease as a possible
diagnosis. Many immunology laboratories receive increasing numbers of test
requests for coeliac serological screening, which would suggest that
doctors do indeed think about this condition. However, the point that
struck me in our audit was how few of these tests were actually positive.
With requests from general practice, only 1.5% of tests were positive for
IgA-TTG antibodies. This is striking for a disease with a prevalence of
1%, and using an assay in which false positive results are common.
Gastroenterologists and Paediatricians only achieved a marginally better
score in our audit. Positive tests were noted in 4.6% and 2.4% of cases
respectively, despite the highly pre-selected patient populations
involved.2
I think that Jones and Sleet identify the key problem with
recognizing coeliac disease – that being the protean and often sub-
clinical manner in which it may present. A truly astounding number of
clinical associations have been linked with this disorder, not mentioning
the issue of whether gluten sensitivity represents a separate entity. We
are not doing very well as doctors in diagnosing this elusive condition
and we should own up to this.
1. Jones R, Sleet S. Easily missed? Coeliac disease. BMJ 2009;338:539
-40.
2. Maher J, Yong PF, Davies ET, Ibrahim MAA. An audit of serological
screening for coeliac disease: real life may not quite mirror research?
The Foundation Years Journal 2009; In press.
3. Feighery L, Collins C, Feighery C, Mahmud N, Coughlan G,
Willoughby R, Jackson J. Anti-transglutaminase antibodies and the
serological diagnosis of coeliac disease. Br J Biomed Sci 2003;60:14-8.
4. Lock RJ, Stevens S, Pitcher MC, Unsworth DJ. Is immunoglobulin A
anti-tissue transglutaminase antibody a reliable serological marker of
coeliac disease? Eur J Gastroenterol Hepatol 2004;16:467-70.
5. Hopper AD, Hadjivassiliou M, Hurlstone DP, Lobo AJ, McAlindon ME,
Egner W, Wild G, Sanders DS. What is the role of serologic testing in
celiac disease? A prospective, biopsy-confirmed study with economic
analysis. Clin Gastroenterol Hepatol 2008;6:314-20.
Competing interests:
None declared
Competing interests: No competing interests
The Pfeiffer Center in Chicago (www.hriptc.org) has treated over
20,000 patients with mental health problems using biochemical therapy in
addition to the standard medication. They have one of the world`s
greatest biochemical databases on mental health with 80-150 test results
on each of those patients. One of their findings is that 4% of those with
psychotic illness have coeliac disease as the only abnormality they found.
I have got IgA endomysial antibodies plus tissue transglutaminase IgA done
on over 100 psychiatric patients and have turned up positive results in some in whom severe depression has been successfully treated with a gluten-free diet. I believe that a test for coeliac disease should become
part of the routine investigations for anybody with a mental health
condition.
Competing interests:
None declared
Competing interests: No competing interests
We welcome your new series “Easily Missed?” but were disappointed
that the article “Easily Missed? Coeliac Disease” failed to highlight the
association between undiagnosed coeliac disease and an increased risk of
foetal growth restriction (FGR).[1] FGR is a major pregnancy complication
responsible for a 5-20 fold increase in perinatal mortality and for
considerable perinatal morbidity. In addition, FGR may have lifelong
consequences ranging from neurodevelopmental delay to an increased risk of
developing hypertension, heart disease and diabetes later in life.[2, 3]
There is a growing body of evidence supporting the association between
undiagnosed coeliac disease and foetal growth restriction with odds ratios
varying between 1.3 and 6. [4, 5] Treatment of maternal celiac disease
reduces the risk of FGR to that of the general population.[6] Two further
studies recently carried out in our unit, one using a high risk Irish
population and, the second, a large Danish population-based study, confirm
this association and highlight the benefits of treatment of coeliac
disease with a gluten free diet. In contrast, other interventions to
reduce the incidence of foetal growth restriction have met with
disappointing results. Therefore, we wish to highlight this association
and the availability of an inexpensive, safe intervention for a condition
associated with such significant morbidity and mortality.
Dr Fergus P McCarthy MRCPI (corresponding author), Clinical Research
Fellow, Anu Research Centre, Cork University Maternity Hospital,
University College Cork, Wilton, Cork
Fergus.mccarthy@ucc.ie (email)
Dr Ali S Khashan PhD, Anu Research Centre, Cork University Maternity
Hospital, University College Cork, Wilton, Cork, Ireland
Professor Eamonn Quigley, M.D. Professor of Medicine and Human
Physiology, Alimentary Pharmabiotic Centre, Dept of Medicine, University
College Cork, Cork, Ireland
Professor Fergus Shanahan. M.D. Professor and Chair of the Department
of Medicine, University College Cork. Director of the Biosciences
Institute, University College Cork, Cork, Ireland.
Dr Louise Kenny PhD, Senior Lecturer, Anu Research Centre, Cork
University Maternity Hospital, University College Cork, Wilton, Cork,
Ireland
Competing interests: None declared
References
1. Jones R, Sleet S. Coeliac disease. BMJ, 2009. 338: p. a3058.
2. Simeoni U, Zetterstrom R. Long-term circulatory and renal
consequences of intrauterine growth restriction. Acta Paediatr. 2005
Jul;94(7):819-24.
3. Osmond C, Barker DJ. Fetal, infant, and childhood growth are
predictors of coronary heart disease, diabetes, and hypertension in adult
men and women. Environ Health Perspect. 2000 Jun;108 Suppl 3:545-53.
4. Ciacci C, Cirillo M, Auriemma G, Di Dato G, Sabbatini F, Mazzacca
G. Celiac disease and pregnancy outcome. The American journal of
gastroenterology. 1996 Apr;91(4):718-22.
5. Salvatore S, Finazzi S, Radaelli G, Lotzniker M, Zuccotti GV.
Prevalence of undiagnosed celiac disease in the parents of preterm and/or
small for gestational age infants. The American journal of
gastroenterology. 2007 Jan;102(1):168-73.
6. Ludvigsson JF, Montgomery SM, Ekbom A. Celiac disease and risk of
adverse fetal outcome: a population-based cohort study. Gastroenterology.
2005 Aug;129(2):454-63.
Competing interests:
None declared
Competing interests: No competing interests
Is is with relief that I read this article. Having presented to my
General Practitioner with ongoing fatigue, I can identify with a diagnosis
that is easily missed. I asked for an iron blood test and as an
afterthought requested a test for coeliac disease, as my mother has it.
After diagnosis by a message on my mobile phone my doctor later told me
she knew nothing about coeliac disease and that they leave that to
dietitians. I found myself a good dietitian and haven't looked back. My
brother has also since been diagnosed. It has not been an easy journey and
I would implore doctors to take this diagnosis seriously and understand
the management of it. A one page summary with links to websites would have
been very reassuring at the time of diagnosis.
Competing interests:
None declared
Competing interests: No competing interests
The article on celiac disease by Roger Jones and Sarah Sleet is well written.[1]
We will do our patients and the health care system a great service if
we put celiac disease on the top of the list of differential diagnoses of
many clinical scenarios.
We all remember that in the medical school we used to call syphilis the
great imitator of neurological disorders.
I believe now celiac disease should assume that title.
I am an endocrinologist and screen for celiac disease likely as frequently
as any gastroenterologist.
Celiac disease is an endocrine cousin:
It causes as much fatigue as hypothyroidism. It causes menstrual
irregularities likely via nutritional deficiencies.It causes miscarriages
(should be thought of in women with recurrent miscarriages), causes
infertility (should be thought of before embarking on costly fertility
treatments), psychiatric problems such as anxiety and depression, poor
memory and concentration via vitamin B12 deficiency or insufficiency.
Celiac disease causes vitamin D deficiency, in itself another disease
mostly missed and it causes severe fatigue, muscle aches and weakness and
tremendous bone pains usually misdiagnosed as fibromyalgia.
Celiac disease should be thought of in investigating osteoporosis with
severe reduction in Z-scores.
Celiac disease causes unexplained elevation in liver enzymes,
including alkaline phosphatase, which could rise partly due to its bone
component due to osteomalacia and vitamin D deficiency.
celiac disease can cause explained seizures and electrolyte imbalances
such as hypocalcemia, when the vitamin D deficiency is severe.
Celiac disease could cause peripheral neuropaty via vitamin B12
deficiency.
Celiac disease can cause skin rash and should be in the differential
diagnosis of such disorder.
Celiac disease is associated with other autoimmune disorders such as type
1 diabetes, and should be in the differential diagnosis of hypoglycemia in
every patient with type 1 diabetes.
Celiac disease can cause low night vision via vitamin A deficiency
and every patient with vitamin A deficiency should be screened.
Patients, especially women with alopecia should be screened for iron and
zinc deficiency, both are nutritional factors in hair growth. Zinc
deficiency can also cause dyguisia, recurrent upper respiratory
infections, and low night vision.
Patients with hypothyroidism whose TSH is always high despite huge doses
of levothyroxine must be screened for celiac disease provided they take
leveothyroxine on an empty stomach without food or coffee or other
medications for at least an hour before breakfast.
Celiac disease could also an underlying cause for elevated
homocysteine and abdominal bacterial overgrowth causing even more
gastrointestinal symptoms such as pain or bloating.
Shirwan Mirza, MD, FACP, FACE
References:
1. Published 19 February 2009, BMJ 2009;338:a3058
Practice
Easily Missed?
Coeliac disease Roger Jones, Wolfson professor of general practice, Sarah Sleet,
chief executive
2. Celiac disease. Guandalini S, Setty M. Curr Opin Gastroenterol. 2008 Nov;24(6):707-12.
3. Celiac disease. Catassi C, Fasano A. Curr Opin Gastroenterol. 2008 Nov;24(6):687-91.
Competing interests:
None declared
Competing interests: No competing interests
Coeliac disease is indeed a great masquerador. The article by Jones
and Sleet of the various unusual manifestations of this condition should
help in considering this diagnosis early and not being ‘easily missed’.
[1] The authors mention iron deficiency as the commonest cause of anaemia
in this condition. However, it is important to bear in mind that other
vitamin deficiencies like that of folic acid and vitamin B12 are not rare
in coeliac disease. [2,3,4] This is especially so because microcytosis or
a low mean cell volume (or MCV) which usually instigates the search for
iron deficiency anaemia (and a diagnosis of coeliac disease) may not be
present in these individuals because of the combined deficiency of iron
and vitamins. Also the lack of response to the treatment of ‘iron
deficiency anaemia’ may be due to the under-correction of the vitamin
deficiencies rather than non-compliance to iron supplementation or non-
adherence to gluten-free diet. Vitamin B12 deficiency may also be
responsible for the neurological abnormalities like ataxia and peripheral
neuropathy, which may be the presenting complaint of celiac disease. [4]
Dermatitis herpetiformis, the cutaneous manifestation of coeliac disease
has also been linked to folic acid and vitamin B12 deficiencies [5,6]. A
rare cause of anaemia in children with coeliac disease is the deficiency
of copper, which can be easily diagnosed by measuring serum copper levels
and rectified by supplementation [7]. Recently the chronic nature of the
condition has led experts to suggest anaemia of chronic disease as another
contributor to anaemia [8]. The predominance of unknown causes of anaemia
in older individuals may also be due to undiagnosed coeliac disease. [9]
References
1. Jones R, Sleet S. Coeliac disease. BMJ. 2009;338:a3058.
2. Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations of
celiac disease.Blood. 2007;109(2):412-21.
3. Bodé S, Gudmand-Høyer E. Symptoms and haematologic features in
consecutive adult coeliac patients. Scand J Gastroenterol. 1996; 31: 54-
60.
4.Dahele A, Ghosh S. Vitamin B12 deficiency in untreated celiac disease.
Am J Gastroenterol. 2001; 96: 745-50.
5. Hoffbrand AV, Douglas AP, Fry L, Stewart JS. Malabsorption of dietary
folate (Pteroylpolyglutamates) in adult coeliac disease and dermatitis
herpetiformis. Br Med J 1970; 4:85–89.
6. Kastrup W, Mobacken H, Stockbrugger R, Swolin B, Westin J.
Malabsorption of vitamin B12 in dermatitis herpetiformis and its
association with pernicious anaemia. Acta Med Scand 1986; 220:261–268.
7. Goyens P, Brasseur D, Cadranel S. Copper deficiency in infants with
active celiac disease. J Pediatr Gastroenterol Nutr 1985; 4:677–680.
8. Hershko C, Patz J. Ironing out the mechanism of anemia in celiac
disease. Haematologica. 2008; 93:1761-5.
9. Freeman HJ. Adult celiac disease in the elderly. World J Gastroenterol.
2008;14(45):6911-4.
Competing interests:
None declared
Competing interests: No competing interests
I read the five pages on coeliac disease in the "Practice" section
and was
surprised to see no mention of the role of dietitians in any of the
articles.
Being French, but British trained, I used to wince at French medical
practice
dropping the ball when it came to patients' dietetic care. However, it
would
appear that the BMJ, mouthpiece of the British medical profession, have
missed a trick when commissioning these three articles.
Coeliac UK states that "following diagnosis of coeliac
disease/Dermatitis
Herpetiformis, it is essential that the patient is referred to a dietitian
for
expert advice on following a gluten-free diet which will be tailored to
the
individual patient... dietitian-led coeliac clinics are evolving as a way
forward
in the management of patients with coeliac disease."
Every coeliac patient in Harrow has access to a dietitian and my
personal
experience is that most of our consultants and GPs make full and early use
of
our service.
References:
www.coeliac.org.uk/healthcare_professionals/management_guidelines/defaul
t.asp
Competing interests:
I am a state registered dietitian
Competing interests: No competing interests
Bleeding manifestations and increased clotting tendency can also be
included under the‘easily missed’ presentations of coeliac disease.
Malabsorption of vitamin-K can lead to the deficiency of vitamin-K
dependent coagulation factors which can manifest as bleeding [1]. Easy
bruising has been reported frequently in coeliac disease although cases
with serious bleeding symptoms like macroscopic haematuria,
intraperitoneal, intramuscular and bilateral adrenal haemorrhage are also
found in the literature [1-7]. Clinical bleeding may still be rare in this
condition, but an abnormal clotting screen is much more common (up to 20%
in untreated cases) and should suggest vitamin-K replacement [2, 8].
Venous thromboembolism can also be the presenting compliant of coeliac
disease and is thought to be related to hyperhomocytsinemia although other
rare clotting factor deficiencies have been suggested [9, 10]. Although
the occurrence of deep vein thrombosis has been noted, the rare portal
vein thrombosis has been associated with coeliac disease suggesting an
enterohepatic cause [11-13].
References
1. Graham DR, Bellingham AJ, Alstead E, Krasner N, Martindale J. Coeliac
disease presenting as acute bleeding disorders.Postgrad Med J. 1982 Mar;
58(677):178-9.
2. Hussaini SH, Ahmed S, Heatley RV. Celiac disease and
hypoprothrombinemia. Nutrition 1999; 15:389–391.
3. Lubel JS, Burrell LM, Levidiotis V. An unexpected cause of macroscopic
haematuria. Med J Aust. 2005; 183: 321-3.
4. Cameron EA, Stewart JA, West KP, Rathbone BJ. Coeliac disease
presenting with intraperitoneal haemorrhage. Eur J Gastroenterol Hepatol.
1998; 10(7):619-20.
5. Chen CS, Cumbler EU, Triebling AT. Coagulopathy due to celiac disease
presenting as intramuscular hemorrhage. J Gen Intern Med. 2007;
22(11):1608-12.
6. Granel B, Rossi P, Frances Y, Henry JF. Bilateral massive adrenal
haemorrhage revealing coeliac disease. QJM 2005; 98: 70-1.
7. Vaynshtein G, Rosenbaum H, Groisman GM, Markel A. Celiac sprue
presenting as severe hemorrhagic diathesis due to vitamin K deficiency.
Isr Med Assoc J. 2004 ; 6(12):781-3.
8. Cavallaro R, Iovino P, Castiglione F, et al. Prevalence and clinical
associations of prolonged prothrombin time in adult untreated coeliac
disease. Eur J Gastroenterol Hepatol 2004; 16:219–223.
9. Gabrielli M, Santoliquido A, Gasbarrini G, Pola P, Gasbarrini A. Latent
coeliac disease, hyperhomocysteinemia and pulmonary thromboembolism: a
close link? Thromb Haemost. 2003; 89(1):203-4.
10. Kallel L, Matri S, Karoui S, Fekih M, Boubaker J, Filali A. Deep
venous thrombosis related to protein S deficiency revealing celiac
disease. Am J Gastroenterol. 2009; 104(1):256-7.
11. Zenjari T, Boruchowicz A, Desreumaux P, Laberenne E, Cortot A,
Colombel JF. Association of coeliac disease and portal venous thrombosis.
Gastroenterol Clin Biol 1995; 19:953–954.
12. Marteau P, Cadranel JF, Messing B, Gargot D, Valla D, Rambaud JC.
Association of hepatic vein obstruction and coeliac disease in North
African subjects. J Hepatol 1994; 20:650–653.
13. Grigg AP. Deep venous thrombosis as the presenting feature in a
patient with coeliac disease and homocysteinaemia. Aust N Z J Med 1999;
29:566–567.
Competing interests:
None declared
Competing interests: No competing interests
If defined just by positive coeliac serology and small bowel biopsy,
perhaps 1% of the population have coeliac "disease", but it is far from
certain that most of these people will benefit from excluding gluten from
their diet. Their untreated condition may confer benefit by reducing their
risk of stroke and ischaemic heart disease (1, 2).
Some of these people, like the rest of us, will be depressed, tired,
and have various other non-gastrointestinal symptoms -- but if those
symptoms do not improve on a gluten-free diet, we may be doing these
patients a disservice insisting that they avoid gluten from now onwards.
Conflict of interest: two close family members -- both over 6ft tall
-- diagnosed with coeliac disease in their eighties. One did subsequently
succumb to small bowel lymphoma, but neither had problems with coronary or
cerebral blood flow.
1. West, Logan, Hill et al. Seroprevalence, correlates, and
characteristics of undetected coeliac disease in England. Gut 2003;52:960
-965.
2. Whorwell, Alderson, Foster, and Wright. Death from ischaemic heart
-disease and malignancy in adult patients with coeliac disease. Lancet
1976 Jul 17;2(7977):113-4.
Competing interests:
None declared
Competing interests: No competing interests
Sensitivity of tissue transglutaminase assays
This is an excellent, concise summary. I would like to point out that
recent data suggests that the sensitivity and specificity of tissue
transglutaminase antibody assays are lower than the quoted 95 and 100%.
Naiyer et al (1) reported sensitivities/specificities between 71.4 and
96.4 % and 87.5 - 100 % respectively. Li et al (2) reported sensitivities
from 69 to 93 % and specificities between 96 - 100 %. Depending upon the
assay and the laboratory, a negative tTG result may not be sufficient to
reliably exclude celiac disease.
1. Naiyer A. et al. Comparison of Commercially Available Serologic
Kits for the Detection of Celiac Disease. J Clin Gastroenterol
2009;43:225–232.
2. Li, M. et al. A Report on the International Transglutaminase
Autoantibody Workshop for Celiac Disease. Am J Gastroenterol 2009; 104:154
– 163.
Competing interests:
None declared
Competing interests: No competing interests