TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
TheraTest Laboratories, Inc.
Dear Colleague:
TheraTest Laboratories, Inc. is proud to announce the launch of a new line of products,
the celiac disease (gluten-sensitive enteropathy)-specific antibody assays:
104-117
EL-tTG™ IgA/IgG (for the detection and measurement of
IgA and IgG
anti-tissue transglutaminase (tTG) antibodies)
104-118
EL-Glia™ IgA/IgG (for the detection and measurement IgA and IgG
anti-gliadin antibodies).
Celiac disease is a unique autoimmune disease: it is induced by gluten, a protein
component of wheat, rye, and barley; however, the autoimmune response destroys the small
intestinal mucosa, and results in malabsorption and nutritional deficiencies. The consequences are
diverse, and the signs and symptoms can be subtle or may mimic other diseases. Rheumatic
presentations are common (1, 2), including arthromyalgias, fatigue, osteoporosis, neuropathy;
moreover, celiac disease is often associated with other autoimmune diseases, mainly thyroid
disorders, type 1 diabetes mellitus, Sjogren’s syndrome and rheumatoid arthritis. The prevalence
of the disease is 1:135 in the general US population, and much higher in the above mentioned
groups. The diagnosis has to be confirmed by gastro-doudenoscopy and positive histology of the
small bowel mucosa. However, as antibody assays (especially the anti-tTG) provide >95%
sensitivity and specificity for diagnosis, serologic screening of every patient seeking
rheumatologist’s care is recommended. If celiac disease is diagnosed, gluten-free diet resolves the
symptoms, prevents late consequences and often results in improving the associated autoimmune
disorder.
We are confident that our new assays will be a useful addition to your laboratory
repertoire and will help you better serve your patients. The attached summary lists the most
important facts about the prevalence, symptoms, diagnosis and management of celiac disease;
however, if you wish to receive more information, don’t hesitate to contact us.
We are looking forward to hearing from you.
Gabriella Lakos MD PhD
Director of Research and Development
Marius Teodorescu MD PhD
President, CEO
September 05, 2008
TEL: 800-441-0771 or 630-627-6069
1
FAX: 630-627-4231
TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
CELIAC DISEASE
INTRODUCTION
Celiac disease (CD) (also called gluten-sensitive enteropathy, GSE) is caused by
intolerance to gluten, the protein of wheat, rye, and barley. CD is characterized by chronic T
cell-mediated inflammation, destruction of the intestinal mucosa and flattening of the
epithelium (“villous atrophy”), resulting in malabsorption. The occurrence of CD has a bimodal
distribution, manifesting both in young children and in adults in the fourth or fifth decades.
Typical symptoms include diarrhea or constipation, abdominal pain, bloating, weight loss, anemia
and fatigue. However, CD can be silent, and most patients have minimal or atypical symptoms,
or are completely asymptomatic (4). Actually, according to a recent study, 57% of newly
diagnosed CD patients had normal body mass index, and 39% of them were even overweight (5).
The prevalence of the disease is high. Recent studies utilizing autoantibody
determinations for screening for unrecognized CD reported a prevalence of 1:85-1:300 (3, 6).
Unfortunately, primary care providers diagnose only 6% of cases (7), partly because of the often
atypical presentation of the disease, partly because of poor awareness. There is a strong genetic
predisposition for CD: HLA-DQ2 is found in 95% of the patients, and most of the remaining
subjects carry HLA-DQ8 (8), which explains the familial occurrence of the disorder. When a
person is identified as having CD, it is recommended that the immediate relatives be also tested.
SYMPTOMS OF CELIAC DISEASE
- GASTROINTESTINAL SYMPTOMS
Diarrhea, constipation, abdominal pain and discomfort, fatigue and weight loss are the
signs of typical, overt CD. However, the disease is often silent or atypical, when gastrointestinal
sypmtoms are not present.
- OSTEOPOROSIS
Among extra-intestinal alterations, bone mass decrease and bone metabolism
derangement are frequently present, and can be the only signs of an otherwise silent celiac disease
(9). The occurrence of celiac disease among osteoporotic individuals is much higher than
that among non-osteoporotic subjects: one study found 3.4% biopsy-proven prevalence (10).
The prevalence of CD in osteoporosis is high enough to justify a recommendation for serologic
screening of all patients with osteoporosis for CD. Treatment of patients with gluten-free diet
TEL: 800-441-0771 or 630-627-6069
2
FAX: 630-627-4231
TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
results in improvement in T scores. Unrecognized CD should also be considered in the
differential diagnosis of osteomalacia (11).
- ANAEMIA
Anemia secondary to malabsorption of iron, folic acid and/or vitamin B12 is a common
complication of celiac disease and many patients present with anemia or have anemia at the time
of diagnosis (12). In a recent study one in 44 patients (2.3%) with microcytic, hypochromic
anemia was diagnosed with histologically confirmed celiac disease (13). Screening for celiac
disease in anemic patients is recommended in clinical practice.
- RHEUMATOLOGIC SYMPTOMS
Celiac disease may resemble a multisystem disorder or may mimic rheumatologic conditions
(1, 2). Fatigue, weakness, non-specific arthralgia, muscle cramps, and myalgia are frequent
symptoms, so screening for celiac disease in patients with what may seem initially to be
fibromyalgia or chronic fatigue syndrome (CFS) is recommended.
- NEUROLOGICAL MANIFESTATIONS
Neurological presentations may include peripheral neuropathy, ataxia or epilepsy (14), and can be
the only symptoms of the disorder. The prevalence of celiac disease as shown by biopsy was at
least 9% in a cohort of 140 patients with idiopathic neuropathy (15). Gluten ataxia has been
shown to be the single most common cause of sporadic idiopathic ataxia, and antibody testing is
essential at first presentation of patients (16).
- REPRODUCTIVE DISORDERS
The wide spectrum of clinical symptoms is partly due to the malnourished state caused by the
malabsorption of macro- and micronutrients and includes delayed puberty, infertility, amenorrhea
and early menopause. Clinical and epidemiological studies show that female patients with celiac
disease are at higher risk of spontaneous abortions, low birth weight of the newborn and reduced
duration of lactation (17). The prevalence of celiac disease in infertile women seems higher
(3.03-2.7%) than in the general population and particularly in the subgroup with unexplained
infertility (4.1-8.0%) (18, 19). Women having recurrent miscarriages or intrauterine growth
retardation could also have subclinical celiac disease (17). Screening for celiac disease should be
part of the diagnostic work-up of infertile women, particularly when no apparent cause can be
ascertained after standard evaluation.
- OTHER SYMPTOMS
Untreated CD can be associated with various other symptoms, including dental enamel defects,
alopecia areata, vitiligo and mood disorders.
TEL: 800-441-0771 or 630-627-6069
3
FAX: 630-627-4231
TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
- ASSOCIATION OF CELIAC DISEASE WITH OTHER CONDITIONS
Celiac disease is more frequent in patients with other autoimmune diseases (3-10 times more),
especially in patients with type 1 diabetes mellitus (DM), thyroid autoimmune and diseases
and Sjogren’s syndrome (20-22). It’s also more prevalent in IgA deficient subjects and in
Down syndrome, and gluten-sensitive enteropathy is almost always present in dermatitis
herpetiformis (23).
- LATE CONSEQUENCES OF UNDIAGNOSED CELIAC DISEASE
Undiagnosed celiac disease can impair the quality of life many ways. Besides the above
mentioned conditions, the most serious outcome is intestinal T cell lymphoma, which is
probably due to the persistent T-cell mediated autoimmune inflammation in the mucosa (24).
Recent studies observed significantly increased risk for other types of non-Hodgkin lymphomas,
too (25). These complications occur mostly in undiagnosed or poorly treated celiac disease, and
can be prevented by adhering to a gluten-free diet.
THE DIAGNOSIS AND MANAGEMENT OF CELIAC DISEASE
The diagnosis is based on the revised criteria of the European Society of Pediatric
Gastroenterology and Nutrition (ESPGAN). These include a positive gut biopsy, showing
histological evidence of CD, plus the demostration of at least two antibodies out of IgA
endomysial antibodies (EMA), IgA anti-gliadin antibodies (AGA) or IgA anti-reticulin antibodies
(ARA). ARA determination (an indirect immunofluorescent test) is not routinely performed any
more in the serological evaluation of CD, as more sensitive and specific assays are available.
Gliadin is a peptide component of gluten, and anti-gliadin antibodies are measured by solid phase
immunoasays. Endomysial antibodies are tested by indirect immunofluorescent assay on monkey
esophagus or human umbilical cord sections. However, in 1997 the tissue transglutaminase
enzyme (tTG) was identified as the target antigen for endomysial antibodies (26), and the
discovery resulted in the development of tTG-based solid phase immunoassays. These show
94-100% sensitivity and 97-99%, specificity, respectively, and are in excellent concordance
with endomysium antibody test results (27), so they became the preferred method. One important
fact is that CD is more prevalent in subjects with selective IgA deficiency. However, as these
patients are not able to produce IgA antibodies, the diagnosis can be overlooked if only IgA
antibodies are tested. It is very important therefore to include at least one IgG antibody test in
the serologic repertoire, preferably anti-tTG (28).
The assays offered by TheraTest simultaneously measure IgA and IgG anti-tTG and
anti-gliadin antibodies to make sure that you will not miss any IgA deficient CD patients.
TEL: 800-441-0771 or 630-627-6069
4
FAX: 630-627-4231
TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
Serologic screening for CD is highly recommended in the following population:
-
first degree relatives of CD patients
-
patients with abdominal pain, diarrhea or constipation
-
patients with fatigue, arthralgias, myalgias, muscle cramps
-
patients with Sjogren’s syndrome, thyreoiditis and type 1 DM
-
patients with anemia
-
patients with osteoporosis
-
women with delayed menarche, fertility problems, recurrent spontaneous abortion or
intrauterine fetal growth retardation
-
patients with mood and neurologic disorders
-
patients with dermatitis herpetiformis
If the result of the screening tests is positive, the patient should be referred to a
gastroenterologist to confirm the diagnosis with small bowel biopsy. Gluten-free diet is the only
effective treatment in CD.
NOTE:
- Patients with CD should be regularly tested for tTG antibodies, as they are useful tools
not only for the diagnosis, but also for the follow-up of patients: the titers of anti-tTG antibodies
rapidly decline in patients adhering to a gluten-free diet (29). Due to the ubiquitous presence of
gluten in commercial food products adherence to diet is difficult. Monitoring antibody levels is
highly recommended.
TEL: 800-441-0771 or 630-627-6069
5
FAX: 630-627-4231
TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Hepburn AL. Adult coeliac disease: Rheumatic presentations are common. BMJ. 2007;335:627.
Caramaschi P, Stanzial A, Volpe A, Pieropan S, Bambara LM, Carletto A, Biasi D. Celiac disease
in a rheumatology unit: a case study. Rheumatol Int. 2008;28:547-51.
Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, Elitsur Y, Green PH, Guandalini S,
Hill ID, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaroli F, Wasserman SS, Murray JA,
Horvath K. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a
large multicenter study. Arch Intern Med. 2003 Feb 10;163(3):286-92.
Schuppan D, Dennis MD, Kelly CP. Celiac disease: epidemiology, pathogenesis, diagnosis, and
nutritional management. Nutr Clin Care. 2005;8(2):54-69.
Dickey W, Kearney N. Overweight in celiac disease: prevalence, clinical characteristics, and
effect of a gluten-free diet. Am J Gastroenterol. 2006;101(10):2356-9.
Rostami K, Mulder CJ, Werre JM, van Beukelen FR, Kerchhaert J, Crusius JB Pena AS,
Willekens FL, Meijer JW. High prevalence of celiac disease in apparently healthy blood donors
suggests a high prevalence of undiagnosed celiac disease in the Dutch population. Scand J
Gastroenterol. 1999;34(3):276-9.
Zipser RD, Farid M, Baisch D, Patel B, Patel D. Physician awareness of celiac disease: a need for
further education. J Gen Intern Med. 2005;20(7):644-6.
Spurkland A, Sollid LM, Ronningen KS, Bosnes V, Ek J, Vartdal F, Thorsby E. Susceptibility to
develop celiac disease is primarily associated with HLA-DQ alleles. Hum Immunol.
1990;29(3):157-65.
Bianchi ML, Bardella MT. Bone and celiac disease. Calcif Tissue Int. 2002 Dec;71(6):465-71.
Stenson WF, Newberry R, Lorenz R, Baldus C, Civitelli R. Increased prevalence of celiac disease
and need for routine screening among patients with osteoporosis. Arch Intern Med.
2005;165(4):393-9.
De Boer WA, Tytgat GN. A patient with osteomalacia as single presenting symptom of glutensensitive enteropathy. Intern Med. 1992;232(1):81-5.
Halfdanarson TR, Litzow MR, Murray JA. Hematological manifestations of celiac disease. Blood.
2006 Sep 14; [Epub ahead of print]
Ransford RA, Hayes M, Palmer M, Hall MJ. A controlled, prospective screening study of celiac
disease presenting as iron deficiency anemia. J Clin Gastroenterol. 2002;35(3):228-33.
Vaknin A, Eliakim R, Ackerman Z, Steiner I. Neurological abnormalities associated with celiac
disease. J Neurol. 2004;251(11):1393-7.
Hadjivassiliou M, Grunewald RA, Kandler RH, Chattopadhyay AK, Jarratt JA, Sanders DS,
Sharrack B, Wharton SB, Davies-Jones GA. Neuropathy associated with gluten sensitivity. Neurol
Neurosurg Psychiatry. 2006;77(11):1262-6.
Hadjivassiliou M, Grunewald R, Sharrack B, Sanders D, Lobo A, Williamson C, Woodroofe N,
Wood N, Davies-Jones A. Gluten ataxia in perspective: epidemiology, genetic susceptibility and
clinical characteristics. Brain. 2003;126(Pt 3):685-91.
Stazi AV, Mantovani A. A risk factor for female fertility and pregnancy: celiac disease. Gynecol
Endocrinol. 2000;14(6):454-63.
Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease. Gut.
1996;39(3):382-4.
Meloni GF, Dessole S, Vargiu N, Tomasi PA, Musumeci S. The prevalence of coeliac disease in
infertility. Hum Reprod. 1999;14(11):2759-61.
Gillett PM, Gillett HR, Israel DM, Metzger DL, Stewart L, Chanoine JP, Freeman HJ. High
prevalence of celiac disease in patients with type 1 diabetes detected by antibodies to endomysium
and tissue transglutaminase. Can J Gastroenterol. 2001;15(5):297-301.
Luft LM, Barr SG, Martin LO, Chan EK, Fritzler MJ. Autoantibodies to tissue transglutaminase in
Sjogren's syndrome and related rheumatic diseases. J Rheumatol. 2003;30(12):2613-9.
Cuoco L, Certo M, Jorizzo RA, De Vitis I, Tursi A, Papa A, De Marinis L, Fedeli P, Fedeli G,
Gasbarrini G. Prevalence and early diagnosis of coeliac disease in autoimmune thyroid disorders.
Ital J Gastroenterol Hepatol. 1999;31(4):283-7.
Reunala T. Dermatitis herpetiformis: coeliac disease of the skin. Ann Med. 1998;30(5):416-8.
TEL: 800-441-0771 or 630-627-6069
6
FAX: 630-627-4231
TheraTest Laboratories, Inc.
1111 N. Main St. Lombard, IL 60148
24. Catassi C, Bearzi I, Holmes GK. Association of celiac disease and intestinal lymphomas and other
cancers. Gastroenterology. 2005;128(4 Suppl 1):S79-86.
25. Smedby KE, Akerman M, Hildebrand H, Glimelius B, Ekbom A, Askling J. Malignant
lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than
enteropathy-type T cell lymphoma. Gut. 2005;54(1):54-9.
26. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D. Identification of
tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997;3(7):797-801.
27. Collin P, Kaukinen K, Vogelsang H, Korponay-Szabo I, Sommer R, Schreier E, Volta U, Granito
A, Veronesi L, Mascart F, Ocmant A, Ivarsson A, Lagerqvist C, Burgin-Wolff A, Hadziselimovic
F, Furlano RI, Sidler MA, Mulder CJ, Goerres MS, Mearin ML, Ninaber MK, Gudmand-Hoyer E,
Fabiani E, Catassi C, Tidlund H, Alainentalo L, Maki M. Antiendomysial and antihuman
recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsyproven European multicentre study. Eur J Gastroenterol Hepatol. 2005;17(1):85-91.
28. Korponay-Szabo IR, Dahlbom I, Laurila K, Koskinen S, Woolley N, Partanen J, Kovacs JB, Maki
M, Hansson T. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for
coeliac disease in selective IgA deficiency. Gut. 2003;52(11):1567-71.
29. Bazzigaluppi E, Roggero P, Parma B, Brambillasca MF, Meroni F, Mora S, Bosi E, Barera G.
Antibodies to recombinant human tissue-transglutaminase in coeliac disease: diagnostic
effectiveness and decline pattern after gluten-free diet. Dig Liver Dis. 2006;38(2):98-102.
TEL: 800-441-0771 or 630-627-6069
7
FAX: 630-627-4231