Transcript Celiac Sprue - Endocrinology

Celiac Sprue: Review of a
Multisystem Disease
Thomas Repas DO FACP CDE
UW Hospital and Clinics Department of Medicine
Section of Endocrinology, Diabetes & Metabolism
H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792
Thursday November 17, 2005
Common Misconceptions
• “Celiac is rare”
• “Celiac is only a disease of children and young
adults”
• “Celiac only occurs in patients of European
descent”
• “All celiac patients have gastrointestinal
symptoms”
• “Serologic testing is unreliable”
• “What does it matter if they have celiac or not?”
Objectives
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History/Background
Prevalence
Pathophysiology
Clinical Manifestations
Associated Disorders
Diagnosis
Management
History of Celiac
Disease
History of Celiac
• Cereal grains were first domesticated from
wild grasses in the Fertile Crescent about
10,000 years ago
Simopoulos AP (ed): Evolutionary Aspects of Nutrition and Health. Diet, Exercise, Genetics and Chronic Disease.
World Rev Nutr Diet. Basel, Karger, 1999, vol 84, pp 19–73
History of Celiac
• Aretaeus from
Cappadochia (now
Turkey) in the 2nd
century AD described a
chronic malabsorptive
condition
• He named this disorder
"koiliakos” which is Greek
for "suffering in the
bowels.”
Booth, CC. History of celiac disease. BMJ 1989; 298:527.
History of Celiac
• The second classical description was in 1888 in a
report entitled "On the Coeliac Affection“ by
Samuel Gee
"to regulate the food is the main part of treatment ...
The allowance of farinaceous foods must be small ...
but if the patient can be cured at all, it must be by
means of diet."
S. Gee: “On the coeliac affection” Saint Bartholomew’s Hospital Reports, London, 1888, 24: 17-20
History of Celiac
• During World War II, celiac
children improved during the
food shortages when bread
was unavailable.
• After the war, symptoms
reoccurred when bread and
cereals were reintroduced.
• Dutch pediatrician Willem K
Dicke recognized and
confirmed this association
between cereal grains and
malabsorption.
Dicke, WK. Simple dietary treatment for the syndrome of GheeHerter. Ned Tijdschr Geneeskd 1941; 85:1715.
DICKE, WK, WEIJERS, HA, VAN DE, KAMER JH. Coeliac disease. II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease.
Acta Paediatr 1953; 42:34.
History of Celiac
• The celiac lesion in the
proximal small intestine was
first described by Paulley in
1954.
• It was learned that celiac
disease and adult nontropical sprue share many of
the same features
• These classic findings are:
– mucosal inflammation
– crypt hyperplasia
– villous atrophy
PAULLEY, JW. Observation on the aetiology of idiopathic steatorrhoea; jejunal and lymph-node biopsies. Br Med J 1954; 4900:1318
RUBIN, CE, BRANDBORG, LL, PHELPS, PC, TAYLOR, HC Jr. Studies of celiac disease. I. The apparent identical and specific nature of the duodenal and proximal jejunal
lesion in celiac disease and idiopathic sprue. Gastroenterology 1960; 38:28
Prevalence of Celiac
Disease
Prevalence of Celiac Disease
• Historically, celiac was thought to be an
uncommon disease
• In the 1950s the prevalence of celiac
disease among Europeans was thought to
range between 1:4000 and 1:8000.
• However, this diagnosis was based upon a
presentation with classic symptoms of
malabsorption
Prevalence of Celiac Disease
• Celiac occurs primarily in whites of northern
European ancestry
• However, it has been reported in many other
groups:
– It has been reported in Indians, Arabs, Hispanics,
Israeli Jews, Sudanese, and people of Cantonese
extraction
– Punjabis and Gujaratis from India who lived in England
developed celiac 2.7 times as often as Europeans
when on a gluten-rich diet
Sher, KS, Fraser, RC, Wicks, AC, et al. High risk of coeliac disease in Punjabis. Epidemiological study in the South Asian and European populations
of Leicestershire. Digestion 1993; 54:178.
Prevalence of Celiac Disease
• In the 1970’s, celiac was recognized that celiac to be
much more common than preciously thought.
Prevalence of Celiac Disease
• In one study, 17,201 Italian school children (aged
6 to 15 years) were recruited from several
regions of Italy and represented 69 percent of
the eligible population.
– Screening was performed with anti-gliadin and antiendomysial antibodies
– Diagnosis was confirmed with small intestines
mucosal biopsy
Catassi, C, Fabiani, E, Ratsch, IM, et al. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac
disease in school-age subjects. Acta Paediatr Suppl 1996; 412:29
Prevalence of Celiac Disease
In this study
– The prevalence of biopsy proven celiac
was 1:184
– The ratio of undiagnosed to diagnosed
celiac disease was a remarkable 7:1
– Most children had minor but significant
nonspecific symptoms
Catassi, C, Fabiani, E, Ratsch, IM, et al. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac
disease in school-age subjects. Acta Paediatr Suppl 1996; 412:29
Prevalence of Celiac Disease
• Many studies have also shown high prevalence
– 1:152 in the Belfast MONICA project evaluating 1,823
participants 1
– 1:256 was noted in a screening study of 1866 Swedish
blood donors 2
– 1:99 in a study of 3654 Finnish students 3
– 1:96 in a study of 3188 Italian school children 4
1. Johnston, SD, Watson, RG, McMillan, SA, et al. Preliminary results from follow-up of a large-scale population survey of antibodies to gliadin, reticulin and endomysium.
Acta Paediatr Suppl 1996; 412:61.
2. Grodzinsky, E. Screening for coeliac disease in apparently healthy blood donors. Acta Paediatr Suppl 1996; 412:36.
3. Maki, M, Mustalahti, K, Kokkonen, J, Kulmala, P. Prevalence of Celiac disease among children in Finland. N Engl J Med 2003; 348:2517.
4. Tommasini, A, Not, T, Kiren, V, et al. Mass screening for coeliac disease using antihuman transglutaminase antibody assay. Arch Dis Child 2004; 89:512
Prevalence of Celiac Disease
• The prevalence of celiac in the US is similar to
Europe
• One large multi-center US study of 13145
subjects consisted of the following:
– 4508 first-degree relatives of patients with celiac
disease
– 1275 second-degree relatives
– 3236 symptomatic patients
– 4126 not-at-risk individuals
Fasano, A, Berti, I, Gerarduzzi, T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study.
Arch Intern Med 2003; 163:286
Prevalence of Celiac Disease
• In this study, the prevalence of celiac
disease was as follows:
– 1:22 in first-degree relatives
– 1:39 in second-degree relatives
– 1:56 in symptomatic patients
– 1:133 in the not-at-risk groups
Fasano, A, Berti, I, Gerarduzzi, T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study.
Arch Intern Med 2003; 163:286
Pathophysiology
of Celiac Disease
Pathophysiology
of Celiac Disease
• Celiac disease as
an immune disorder
that is triggered by
an environmental
agent (the gliadin
component of
gluten) in genetically
predisposed
individuals
Kagnoff, MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am 1992; 21:405.
Schuppan, D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119:234.
Pathophysiology
of Celiac Disease
Grain protein exists in four general storage forms which
are categorized by their solubility characteristics:
• Prolamins (soluble in ethanol)
• Glutenins (partially soluble in dilute acid or alkali
solutions)
• Globulins (soluble in 10 percent NaCl)
• Minor albumins (soluble in water)
Glutens specifically are the prolamins and the glutenins
Bernardin, JE, Saunders, RH, Kasarda, DD. Absence of carbohydrate in coeliac toxic A-gliadin. Cereal Chem 1976; 53:612.
Freedman, AR, Galfre, G, Gal, E, et al. Western immunoblotting of cereal proteins with monoclonal antibodies to wheat gliadin to investigate coeliac disease. Int Arch Allergy Appl Immunol 1988; 85:346.
Troncone, R, Auricchio, S, De Vincenzi, M, et al. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Pediatr Gastroenterol Nutr 1987; 6:346.
Vader, LW, Stepniak, DT, Bunnik, EM, et al. Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology 2003; 125:1105
Taxonomy of Grains
Gliadins Secalins
Hordeins
Avenins
Zeins
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Pathophysiology
of Celiac Disease
• The pathophysiology of gliadin toxicity in celiac
patients is poorly understood
• One hypothesis is that similarities between
gliadin proteins and certain enteral pathogens
may result in the immunologic response to
antigens in gluten.
Kagnoff, MF, Paterson, NY, Kumar, PJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987;
28:995
Pathophysiology
of Celiac Disease
• Kagnoff et al suggested that the alpha fraction of
gliadin demonstrated an amino acid region that
was homologous to the 54KDa E1b protein coat
of adenovirus 12
• The authors postulated that exposure to this
virus in a susceptible person may be potentially
be involved in the pathogenesis of celiac disease
Kagnoff, MF, Paterson, NY, Kumar, PJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987;
28:995
Pathophysiology
of Celiac Disease
• Other studies, however, have failed to
show an association with the presence
of celiac sprue and serum antibody
titers to the adenovirus 12 protein
Nilsen, EM, Lundin, KE, Krajci, P, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated
by interferon gamma. Gut 1995; 37:766
Pathophysiology
of Celiac Disease
• The current hypotheses:
– Gliadin-sensitive T cells in genetically
predisposed individuals recognize glutenderived peptide epitopes and develop an
inflammatory response which produces
mucosal damage
Nilsen, EM, Lundin, KE, Krajci, P, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated
by interferon gamma. Gut 1995; 37:766
Pathophysiology
of Celiac Disease
• Genetic factors play an important role- there is
significantly increased risk of celiac among family
members
• A close association with the HLA-DQ2 and/or DQ8
gene locus has been recognized
• HLA-DQ2 is found in 98 percent of celiac patients
from Northern Europe.
• However, ~25% of “normal” individuals in this
population will also demonstrate HLA-DQ2
Kagnoff, MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am 1992; 21:4
Schuppan, D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119:234.
Petronzelli, F, Bonamico, M, Ferrante, P, et al. Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet 1997; 61:307
Houlston, RS, Ford, D. Genetics of coeliac disease. QJM 1996; 89:737.
Houlston, RS, Tomlinson, IP, Ford, D, et al. Linkage analysis of candidate regions for coeliac disease genes. Hum Mol Genet 1997; 6:1335
Current Model for Pathogenesis of
Celiac Disease
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Pathophysiology
of Celiac Disease
• HLA class II molecules are expressed on the
surface of antigen-presenting cells
• They can bind to and subsequently present
“foreign” peptides to populations of CD4 T
cells that recognize the DQ2- or DQ8-peptide
complex
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Role of Tissue Transglutaminase
• Tissue transglutaminase can deamidate
glutamine, converting glutamine to negatively
charged glutamic acid
• This renders these peptides better binders to the
disease relevant DQ2 or DQ8 molecules
• Once bound to DQ2 or DQ8, the DQ-“gluten”
peptide complexes activate DQ2 or DQ8
restricted T cells
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Gluten peptide binding in the peptide
binding groove of a DQ2 heterodimer
•Gluten peptides form left-handed polyproline II helixes that are a preferred conformation
for binding in the peptide-binding groove of HLA class II molecules.
•Pockets at several positions have a preference for negatively charged residues such as
those formed in gluten peptides upon deamidation
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Activation of DQ-restricted T cells
in Celiac Disease
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Celiac Disease: Clinical
Manifestations
Celiac Disease: Clinical
Manifestations in Children
The classical presentation is in children after
weaning and introduction of cereals into the
diet:
• Failure to thrive
• Apathy
• Pallor
• Anorexia
• Muscle wasting with generalized hypotonia
• Abdominal bloating and distention
• Soft, bulky, clay-colored, offensive stools
Celiac Disease: Clinical
Manifestations
• As our understanding of celiac improved
and serologic testing has become
available, subclinical forms of the
disease have been recognized
Celiac Disease: Clinical
Manifestations in Children
Symptoms and signs at presentation
Overall prevalence (%)
Iron deficiency with anemia
29
Iron deficiency without anemia
27
Recurrent Abdominal Pain
24
Mood Changes
17
Recurrent Aphthous Stomatitis
11
Poor appetite
10
Recurrent diarrhea
9
Short stature
7
Abdominal distension
5
Constipation
2
Pubertal delay
2
Hypoalbuminemia
2
Catassi, C, et al Acta Paediatr 1996; 412(suppl):29.
Celiac Disease: Clinical
Manifestations in Adults
In a study of 1138 people with biopsy–proven celiac
disease:
• Majority of individuals were diagnosed in their 4th to
6th decades.
• Women predominated (2.9:1)- the female
predominance was less marked in the elderly.
• Diarrhea was the main presenting symptom occurring
in 85%.
• 36% had a previous diagnosis of irritable bowel
syndrome.
• Symptoms were present a mean of 11 years before
diagnosis.
Green PHR, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol
2001;96:126–131.
Celiac Disease: Clinical
Manifestations in Adults
In a population-based study from Minnesota,
Murray et al noted a 10-fold increase in the
incidence of celiac disease from 1950 to 2001.
• The clinical severity of the disease decreased,
with fewer people with diarrhea and weight loss
at presentation.
• Only 54% had diarrhea at diagnosis, 34%
abdominal pain and 30% bloating.
• Obesity was present in 27%.
Murray JA, et al. Trends in the incidence and clinical features of celiac disease in a North American community, 1950-2001. Clin Gastroenterol
Hepatol 2003;1:19–27.
Spectrum of Celiac Disease
Few if any GI symptoms
Fatigue
Depression, irritability
Menstrual irregularity
Weakness
Infertility
Growth Disturbance
Neurologic Complaints
Marked GI symptoms
Diarrhea
Bulky, Pale, Foul stools
Abdominal Distension, Bloating
Abdominal cramps
Weight loss
Loss of or increased appetite
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
Classification of Celiac Disease
• Classical celiac disease
• Celiac disease with atypical
symptoms
• Silent celiac disease
• Latent celiac disease
NATIONAL INSTITUTES OF HEALTH, CONSENSUS DEVELOPMENT CONFERENCE STATEMENT: Celiac Disease.
June 28–30, 2004
Celiac Disease:
Associated Disorders
Celiac Disease: Associated
Disorders
• Dermatitis Herpetiformis
• Iron deficiency anemia
• Osteoporosis, Osteomalacia and Vitamin D
deficiency
• Malignancies
• Type 1 diabetes
• Other autoimmune endocrine disorders
• Neuropsychologic Features
• Others (Downs syndrome, IgA deficiency,
rheumatologic disorders)
Celiac Disease: Dermatitis
Herpetiformis
• Symmetric vesicles,
crusts and erosions
distributed over the
extensor areas of the
elbows, knees,
buttocks, shoulders
and scalp, with a
tendency to grouping
of individual lesions.
PRUESSNER, HT. Detecting Celiac Disease in Your Patients. 1998 by the American Academy of Family Physicians
University of Texas Medical School at Houston
Celiac Disease: Dermatitis
Herpetiformis
• It has been reported
that up to 10 percent of
individuals with celiac
will also have dermatitis
herpetiformis
American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526.
Guidetti, CS, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders,Gut
2001;49:502–505
Celiac Disease: Other Skin
Disorders
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Acquired icthyosis
Cutaneous amyloid
Cutaneous vasculitis
Eczema
Epidermal necrolysis
Nodular prurigo
Pityriasis rubra pilara
Pustular dermatitis
American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526.
Celiac Disease: Iron Deficiency
Anemia
• In a study of 227 patients with biopsy–proven
celiac disease- iron-deficiency anemia was
the mode of presentation in 8%1
• In a Mayo Clinic study, celiac disease was
identified as the cause of iron deficiency in
15% of those undergoing endoscopic
assessment for iron deficiency.2
• In a prospective study of adults, mean age in
their 50s, Karnum et al found 2.8% to have
celiac disease.3
1. Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac disease. Dig Dis Sci 2003;48:395–398.
2. Oxentenko AS, et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002;97:933–938.
3. Karnam US, et al. Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study. South Med J 2004;97:30–34.
Celiac Disease: Osteoporosis
• 840 individuals were evaluated by serologic
screening for celiac disease at the Washington
University Bone Clinic
– 266 with osteoporosis
– 574 without osteoporosis
• Individuals with positive serologic test were
offered endoscopic intestinal biopsy
• The prevalence of biopsy-proven celiac disease
was
– 3.4% in individuals with osteoporosis
– 0.2% in individuals without osteoporosis
Stenson WF et al. Increased Prevalence of Celiac Disease and Need for Routine Screening Among Patients With Osteoporosis
ARCH INTERN MED/VOL 165, FEB 28, 2005
Celiac Disease: Osteoporosis
Stenson WF et al. Increased Prevalence of Celiac Disease and Need for Routine Screening Among Patients With Osteoporosis
ARCH INTERN MED/VOL 165, FEB 28, 2005
Celiac Disease: Osteoporosis
P=0.02
Treatment of the
patients with celiac
disease with a
gluten-free diet for
1 year resulted
in improvement in
T scores.
Stenson WF et al. Increased Prevalence of Celiac Disease and Need for Routine Screening Among Patients With Osteoporosis
ARCH INTERN MED/VOL 165, FEB 28, 2005
Celiac Disease: Vitamin D
Deficiency
• 255 women with
osteoporosis
• 53 women tested
positive for tTG ab
• Prevalence of
serological disease
9.4%
Nuti, R et al. Prevalence of undiagnosed coeliac syndrome in osteoporotic women. Journal of Internal Medicine 2001;
250: 361±366
Celiac Disease: Vitamin D
Deficiency
Nuti, R et al. Prevalence of undiagnosed coeliac syndrome in osteoporotic women. Journal of Internal Medicine 2001;
250: 361±366
Celiac Disease: Malignancies
Malignancy
All cancers
Overall
Relative Risk
2 to 3
Enteropathy associated T-cell
lymphomas
30 to 40 (w/o
gluten free
diet)
Small intestinal
adenocarcinoma
83
Mouth, pharynx,
esophagus cancer
American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526.
23 (w/o gluten
free diet)
Celiac Disease: Type 1 Diabetes
• An association between CD and type 1 diabetes
mellitus (T1DM) has been recognized for decades
• Several studies in children and adults, have shown
that there is a 1.5% to 7% prevalence of CD in type
1 diabetes
• A community-based study of type 1 diabetics of all
ages in Olmsted County, MN, revealed that 6.5%
had celiac disease.
Talal AH, et al . Celiac disease in an adult population with insulin-dependent diabetes mellitus: use of endomysial antibody testing. Am J
Gastroenterol 1997;92:1280.
Fraser-Reynolds KA, et al. Use of immunoglobulin A-antiendomysial antibody to screen for celiac disease in North American children with type 1
diabetes. Diabetes Care 1985;1009:21.
Koletzko S, et al . Prevalence of coeliac disease in diabetic children and adolescents: a multicentre study. Eur J Pediatr 1998;148:113.
Sigurs N, et al . Prevalence of coeliac disease in diabetic children and adolescents in Sweden. Acta Paediatrica 1993;82:748.
Collin P, et al. High frequency of coeliac disease in adult patients with type-I diabetes. Scand J Gastroenterol 1989;24:81.
Celiac Disease: Type 1 Diabetes
• Untreated celiac disease may increase risk of
developing type 1 diabetes
– Autoantibodies directed against islet cells are frequently
present in untreated CD but disappear with the glutenfree diet
– Patients in whom CD was identified and treated in early
childhood had a lower rate of developing diabetes than
children in whom CD was diagnosed later in childhood
or as adults
Ventura AMG, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group
for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999;117:297.
Ventura A, Neri E, Ughi C, Leopaldi A, Citta A, Not T. Glutendependent diabetes-related and thyroid-related autoantibodies in patients with
celiac disease. J Pediatr 2000;137:263.
Celiac Disease: Autoimmune
Thyroid Disease
• In one study of 83 patients with autoimmune
thyroid disease found a frequency of celiac
disease of 4.8 percent
• An epidemiologic study of 335 patients
diagnosed with celiac disease between
1980 and 1990 determined that 5.4 percent
of the patients with celiac disease also had
autoimmune thyroid disease
Collin P, Reunala T, Pukkala E, Laippala P, Keyrilainen O, Pasternack A. Coeliac disease--associated disorders and survival. Gut 1994;35:1215-8.
Collin P, Salmi J, Hallstrom O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol 1994;130:137-40
Celiac Disease: Other Autoimmune
Endocrine Disorders
In study of 605 controls and 422 patients (aged 16–84 years):
30% of adult patients with CD had at least one AI disease with
an overall 2–3-fold higher frequency than controls.
Guidetti, CS, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders,Gut 2001;49:502–
505
Celiac Disease:
Neuropsychologic Features
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Depression- 10.6%
Epilepsy- 3.5%
Migraine headaches- 3.2%
Anxiety- 2.6%
Suicidal tendency- 2.1%
Carpal tunnel- 1.8%
Myopathy- 1.5%
Holmes, JKT, Acta Paediatr 1996; 412 (Suppl): 68
Celiac Disease:
Neuropsychologic Features
• Computed
tomographic scan
showing occipital
calcification in a
patient with celiac
disease and
epilepsy
PRUESSNER, HT. Detecting Celiac Disease in Your Patients. 1998 by the American Academy of Family Physicians
University of Texas Medical School at Houston
Celiac Disease:
Neuropsychologic Features
• A review of 39 published articles on
patients with celiac disease, cerebral
calcifications and epilepsy concluded
that the exact pathogenic process was
unknown
Cuvellier JC, Vallee L, Nuyts JP. Celiac disease, cerebral calcifications and epilepsy syndrome. Arch Pediatr 1996;3:1013-9
Diagnosis of Celiac
Disease
Diagnosis of Celiac Disease
• Clinical Findings
• Small Intestines
Mucosal Biopsy
• Gluten Re-challenge
• Serologic testing
Diagnosis: Small Bowel
Endoscopy
Normal
Celiac
Diagnosis: Small Bowel
Endoscopy
Histologic Findings of Celiac
Normal Jejunum
Virginia Commonwealth Univ, Richmond, Virginia Celiac Disease (Gluten-Induced Enteropathy) 65000-45800-F2923
Celiac
Histologic Findings of Celiac
Normal
Flattened Villi in Celiac
Histologic Findings of Celiac
• The lamina propria
shows a marked
increase in the
number of plasma
cells and lymphocytes
and transepithelial
migration of
lymphocytes across
the surface epithelium
(arrow) is common.
Virginia Commonwealth Univ, Richmond, Virginia Celiac Disease (Gluten-Induced Enteropathy) 65000-45800-F2923
Intestinal Lesions of Celiac Disease
Marsh, MN, Gastroenterology 1992; 102:330.
Histologic Findings of Celiac
Virginia Commonwealth Univ, Richmond, Virginia Celiac Disease (Gluten-Induced Enteropathy) 65000-45800-F2923
Other Causes of Villous Atrophy
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•
•
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Bacterial Overgrowth
Crohn’s disease
Cow’s milk protein intolerance (children)
Eosinophilic gastroenteritis
Giardiasis
Lymphoma
Peptic duodenitis
Post gastroenteritis
Tropical sprue
Zollinger Ellison syndrome
American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526.
Diagnosis of Celiac: Gluten
Rechallenge
• Gluten Rechallenge- improvement in symptoms
and histology with gluten avoidance with a
documented return of these features upon gluten
reintroduction.
• May be performed by consuming 10 g of gluten
per day (an amount contained in four slices of
regular bread) for four to six weeks.
• One hazard of rechallenge is development of
fulminant diarrhea, with dehydration, acidosis, and
other metabolic disturbances ("gliadin shock").
KRAINICK, HG, DEBATIN, F, GAUTIER, E, et al. [Additional research on the injurious effect of wheat flour in celiac disease.I. Acute gliadin reaction (gliadin
shock).]. Helv Paediatr Acta 1958; 13:432
Diagnosis of Celiac: Gluten
Rechallenge
• Per the European Society of Paediatric
Gastroenterology and Nutrition guidelines:
gluten rechallenge is not required in patients
with improvement in symptoms, histology,
and a decline in the antibody titers.
• Gluten rechallenge is also considered to be
unnecessary by the 2004 consensus
statement issued by the National Institutes of
Health.
National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at http://consensus.nih.gov.
Walker-Smith, JA, Guandalini, S, Schmitz, J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909.
Diagnosis of Celiac: Serologic
Testing
• Some of the serologic tests used to
diagnose celiac:
– IgA and IgG antigliadin antibodies
– IgA endomysial antibodies
– IgA and IgG tissue transglutaminase
antibodies
– Anti reticulin antibodies (no longer used)
Diagnosis of Celiac:
Antigliadin Antibodies
• IgA and IgG antigliadin antibody tests are
considered less accurate, less sensitive and less
specific than other serologic tests.
• Frequent false positive results (15 to 20 %) often
leads to unnecessary endoscopy with biopsy
• Therefore, antigliadin antibody is no longer
recommended for initial diagnostic evaluation or
screening
National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at http://consensus.nih.gov.
Walker-Smith, JA, Guandalini, S, Schmitz, J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909.
Diagnosis of Celiac: IgA
Endomysial Antibodies
• Endomysial antibodies bind to connective tissue
surrounding smooth muscle cells
• IgA endomysial antibodies bind to the
endomysium, producing a characteristic staining
pattern, which is visualized by indirect
immunofluorescence.
• IgA endomysial antibody testing is moderately
sensitive and highly specific for untreated celiac
disease
National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at http://consensus.nih.gov.
Walker-Smith, JA, Guandalini, S, Schmitz, J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909.
Diagnosis of Celiac: Anti-tissue
Transglutaminase Antibodies
• The antigen against which antiendomysial
antibodies are directed is a tissue
transglutaminase (tTG)
• IgA anti-tTG antibodies testing by ELISA are
considered easier to perform and less costly than
the immunofluorescence assay used to detect IgA
endomysial antibodies.
• Anti-tTG antibodies are both highly sensitive and
specific
National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at http://consensus.nih.gov.
Walker-Smith, JA, Guandalini, S, Schmitz, J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909.
Diagnosis of Celiac: Serologic Testing
•IgA antigliadin antibodies
•Sensitivity 80 to 90 %
•Specificity 85 to 95 %
•IgA endomysial antibodies
•Sensitivity 85 to 98 %
•Specificity 97 to 100 %
•IgA tissue transglutaminase antibodies
•Sensitivity 90 to 98 %
•Specificity 95 to 97 %
Kelly, CP. Coeliac disease: Non-invasive tests to screen for gluten sensitive enteropathy and to monitor response to dietary therapy. Dublin University, Trinity College, Dublin 1995.
Kelly, CP, Feighery, CF, Gallagher, RB, et al. Mucosal and systemic IgA anti-gliadin antibody in celiac disease. Contrasting patterns of response in serum, saliva, and intestinal secretions. Dig Dis Sci
1991; 36:743.
Diagnosis of Celiac: IgA
• IgA deficiency is more common in celiac disease
(2 to 5 percent) than in the general population
(<0.5 percent).
• IgA EMA and IgA tTG will be falsely negative in
patients with IgA deficiency.
• Thus, total serum IgA should be also measured
in addition to IgA EMA or IgA tTG
• If total IgA levels are abnormally low, consider
IgG-based assay
Diagnosis of Celiac Disease
Probability < 2 to 5 percent
Obtain IgA endomysial or tTG Ab
and serum IgA level
Positive
Small bowel biopsy
Negative
Diagnosis excluded
{
Probability > 2 to 5 percent
IgA endomysial or tTG Ab + IgA
AND Small bowel biopsy
Histology -
Review and/or
repeat biopsy
-
Histology +
Both
positive
Serology +
+
TREAT
•Family history
•Unexplained iron deficiency anemia
•Steatorrhea or other GI symptoms
•Failure to thrive
•Type 1 diabetes mellitus or other
associated disorders
•Other symptoms
Both
negative
Serology -
-
Rule out
other
causes of
villous
atrophy
+
Diagnosis
excluded
Management of Celiac
Disease
Management of Celiac Disease
• Gluten avoidance is the mainstay of treatment
• Prior to the introduction of a strict gluten-free
diet, prognosis was very poor
• Mortality was 12 percent in one retrospective
study of 544 children
Hardwick, C. Prognosis in coeliac disease. Arch Dis Child 1939; 14:279
Management of Celiac Disease
In general, the following advice can be
given to all patients:
• Foods containing wheat, rye, and barley should be
avoided.
• Soybean or tapioca flours, rice, corn, buckwheat, and
potatoes are safe.
• Read labels on prepared foods and condiments
carefully (many stabilizers or emulsifiers contain gluten)
• Dairy products may need to be avoided initially- many
patients have secondary lactose intolerance.
Foods That May Contain Gluten
•
•
•
•
•
•
Bouillon Cubes
Canned soups
Catsup
Cheese spreads
Chips and dips mixes
Hot chocolate mixes
or cocoa
• Ice cream
• Luncheon meats
• Meat sauces (soy,
Worcestershire, etc)
•
•
•
•
•
•
•
•
•
Mustard
Non-dairy creamer
Peanut butter
Processed canned
meats and poultry
Salad dressing
Soup mixes
Tomato sauces
Wieners and other
sausages products
Yogurt with fruit
Trier, JS. Celiac Sprue and refractory sprue. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 6 th Ed, Feldman, M,
Scharscmidt, BF, Sleisenger, MH (Eds), Saunders, Philadelphia 1998. p. 1568
What about oats?
•Whether oats may be
included in a gluten free
diet is controversial
• Some studies suggest
that oats can be tolerated
without disease
recurrence
Taxonomy of Grains
Gliadins Secalins
Hordeins
Avenins
Zeins
KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18
What about oats?
• In one study, 52 adults with celiac disease in
remission and 40 with newly diagnosed celiac
disease were randomly assigned to a gluten-free
diet without oats, or a gluten-free diet with a total
daily consumption of 50 to 70 g of oats.
• At the end of one year, no significant difference
were observed in the nutritional status,
symptoms, or laboratory or histologic measures
between the two groups
Janatuinen, EK, Pikkarainen, PH, Kemppainen, TA, et al. A comparison of diets with and without oats in adults with celiac disease. N Engl J
Med 1995; 333:1033
What about oats?
• Another controlled trial involved 39 adults who were
randomly assigned to either a gluten-free diet with 50 g
of oat-containing products daily or to a gluten-free diet
without oats for one year.
• Quality of life scores were similar between the groups,
and there were no significant differences in the villous
structure of small bowel biopsies.
• However, patients consuming oats had significantly more
gastrointestinal symptoms (including diarrhea and
constipation) and had a significantly higher density of
intraepithelial lymphocytes
Peraaho, M, Kaukinen, K, Mustalahti, K, et al. Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A
randomized study. Scand J Gastroenterol 2004; 39:27
What about oats?
• Limit oat consumption to 50 to 60 g/day
(approximately 2 oz) in patients with mild disease
or whose disease is in remission after a stringent
gluten-free diet.
• Patients should be followed carefully for clinical or
serologic evidence of disease recurrence after
reintroducing oats.
• Patients with severe disease should avoid oats
altogether
Lundin, KE, Nilsen, EM, Scott, HG, et al. Oats induced villous atrophy in coeliac disease. Gut 2003; 52:1649.
Thompson, T. Gluten contamination of commercial oat products in the United States. N Engl J Med 2004; 351:2021.
Hoffenberg, EJ, Haas, J, Drescher, A, et al. A trial of oats in children with newly diagnosed celiac disease. J Pediatr 2000; 137:361
Monitoring Adherence by
Serologic Testing
•Monitoring response to gluten free diet by
measuring levels of antibodies is controversial
•Variations in test results between assays may be
substantial and make interpretation difficult or
impossible.
•It is unknown if monitoring antibodies improves
outcomes or is cost effective
NATIONAL INSTITUTES OF HEALTH, CONSENSUS DEVELOPMENT CONFERENCE STATEMENT: Celiac Disease.
June 28–30, 2004
Management of Celiac Disease
N=20
N=10
Serum IgA antigliadin titers at diagnosis and after 12 – 16 months of dietary therapy
Monitoring Adherence by
Serologic Testing
• A pretreatment antibody level should be determined at
the time of diagnosis.
• Serologic testing is of no use if antibody levels are not
elevated prior to therapy.
• Exclusion of gluten from the diet results in a gradual
decline in serum IgA antigliadin and IgA tTG levels.
• A normal baseline value is typically reached within three
to six months.
• If the levels do not fall as anticipated, the patient may be
continuing to ingest gluten either intentionally or
inadvertently
Kelly, CP. Coeliac disease: Non-invasive tests to screen for gluten sensitive enteropathy and to monitor response to dietary therapy. Dublin University,
Trinity College, Dublin 1995.
Summary: Management of Celiac
Disease
A recent NIH statement recommended the following strategy
when managing individuals with celiac disease:
•
•
•
•
Consultation with a skilled dietitian
Education about the disease
Lifelong adherence to a gluten-free diet
Identification and treatment of nutritional
deficiencies
• Access to an advocacy group
• Continuous long-term follow-up by a
multidisciplinary team
NATIONAL INSTITUTES OF HEALTH, CONSENSUS DEVELOPMENT CONFERENCE STATEMENT: Celiac Disease.
June 28–30, 2004
Questions?