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Celiac Sprue: Review of a Multisystem Disease Thomas Repas

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Title: Celiac Sprue: Review of a Multisystem Disease Thomas Repas


1
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
2
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?

3
Objectives
  • History/Background
  • Prevalence
  • Pathophysiology
  • Clinical Manifestations
  • Associated Disorders
  • Diagnosis
  • Management

4
History of Celiac Disease
5
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 1973
6
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
298527.
7
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
Bartholomews Hospital Reports, London, 1888, 24
17-20
8
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 851715. 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
4234.
9
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
    non-tropical 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 49001318 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 3828
10
Prevalence of Celiac Disease
11
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
    14000 and 18000.
  • However, this diagnosis was based upon a
    presentation with classic symptoms of
    malabsorption

12
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 54178.
13
Prevalence of Celiac Disease
  • In the 1970s, celiac was recognized that celiac
    to be much more common than preciously thought.

14
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
    anti-endomysial 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 41229
15
Prevalence of Celiac Disease
  • In this study
  • The prevalence of biopsy proven celiac was 1184
  • The ratio of undiagnosed to diagnosed celiac
    disease was a remarkable 71
  • 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 41229
16
Prevalence of Celiac Disease
  • Many studies have also shown high prevalence
  • 1152 in the Belfast MONICA project evaluating
    1,823 participants 1
  • 1256 was noted in a screening study of 1866
    Swedish blood donors 2
  • 199 in a study of 3654 Finnish students 3
  • 196 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 41261. 2. Grodzinsky, E. Screening
for coeliac disease in apparently healthy blood
donors. Acta Paediatr Suppl 1996 41236. 3.
Maki, M, Mustalahti, K, Kokkonen, J, Kulmala, P.
Prevalence of Celiac disease among children in
Finland. N Engl J Med 2003 3482517. 4.
Tommasini, A, Not, T, Kiren, V, et al. Mass
screening for coeliac disease using antihuman
transglutaminase antibody assay. Arch Dis Child
2004 89512
17
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 163286
18
Prevalence of Celiac Disease
  • In this study, the prevalence of celiac disease
    was as follows
  • 122 in first-degree relatives
  • 139 in second-degree relatives
  • 156 in symptomatic patients
  • 1133 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 163286
19
Pathophysiology of Celiac Disease
20
Pathophysiologyof 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 21405. Schuppan, D. Current concepts
of celiac disease pathogenesis. Gastroenterology
2000 119234.
21
Pathophysiologyof 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 53612. 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
85346. 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
6346. Vader, LW, Stepniak, DT, Bunnik, EM, et
al. Characterization of cereal toxicity for
celiac disease patients based on protein homology
in grains. Gastroenterology 2003 1251105
22
Taxonomy of Grains
Gliadins
Secalins
Hordeins
Avenins
Zeins
KAGNOFF, MF. Overview and Pathogenesis of Celiac
Disease GASTROENTEROLOGY 2005128S10S18
23
Pathophysiologyof 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 28995
24
Pathophysiologyof 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 28995
25
Pathophysiologyof 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 37766
26
Pathophysiologyof Celiac Disease
  • The current hypotheses
  • Gliadin-sensitive T cells in genetically
    predisposed individuals recognize gluten-derived
    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 37766
27
Pathophysiologyof 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 214 Schuppan, D. Current concepts of
celiac disease pathogenesis. Gastroenterology
2000 119234. 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 61307 Houlston,
RS, Ford, D. Genetics of coeliac disease. QJM
1996 89737. Houlston, RS, Tomlinson, IP, Ford,
D, et al. Linkage analysis of candidate regions
for coeliac disease genes. Hum Mol Genet 1997
61335
28
Current Model for Pathogenesis of Celiac Disease
KAGNOFF, MF. Overview and Pathogenesis of Celiac
Disease GASTROENTEROLOGY 2005128S10S18
29
Pathophysiologyof 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 2005128S10S18
30
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 2005128S10S18
31
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 2005128S10S18
32
Activation of DQ-restricted T cells in Celiac
Disease
KAGNOFF, MF. Overview and Pathogenesis of Celiac
Disease GASTROENTEROLOGY 2005128S10S18
33
Celiac Disease Clinical Manifestations
34
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

35
Celiac Disease Clinical Manifestations
  • As our understanding of celiac improved and
    serologic testing has become available,
    subclinical forms of the disease have been
    recognized

36
Celiac Disease Clinical Manifestations in
Children
Catassi, C, et al Acta Paediatr 1996
412(suppl)29.
37
Celiac Disease Clinical Manifestations in Adults
  • In a study of 1138 people with biopsyproven
    celiac disease
  • Majority of individuals were diagnosed in their
    4th to 6th decades.
  • Women predominated (2.91)- 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 200196126131.
38
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 200311927.
39
Spectrum of Celiac Disease
Few if any GI symptoms
Marked GI symptoms
Fatigue Depression, irritability Menstrual
irregularity Weakness Infertility Growth
Disturbance Neurologic Complaints
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 2005128S10S18
40
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 2830, 2004
41
Celiac Disease Associated Disorders
42
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)

43
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
44
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 200149502505
45
Celiac Disease Other Skin Disorders
  • 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.
46
Celiac Disease Iron Deficiency Anemia
  • In a study of 227 patients with biopsyproven
    celiac disease- iron-deficiency anemia was the
    mode of presentation in 81
  • 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 200348395398. 2. Oxentenko AS, et
al. The insensitivity of endoscopic markers in
celiac disease. Am J Gastroenterol
200297933938. 3. Karnam US, et al. Prevalence
of occult celiac disease in patients with
iron-deficiency anemia a prospective study.
South Med J 2004973034.
47
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
48
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
49
Celiac Disease Osteoporosis
P0.02
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
50
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 361366
51
Celiac Disease Vitamin D Deficiency
Nuti, R et al. Prevalence of undiagnosed coeliac
syndrome in osteoporotic women. Journal of
Internal Medicine 2001 250 361366
52
Celiac Disease Malignancies
American Gastroenterological Association,
Ciclitra, PJ, Gastroenterology 2001 120 1526.
53
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 1997921280. 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 1985100921. Koletzko S, et al . Prevalence
of coeliac disease in diabetic children and
adolescents a multicentre study. Eur J Pediatr
1998148113. Sigurs N, et al . Prevalence of
coeliac disease in diabetic children and
adolescents in Sweden. Acta Paediatrica
199382748. Collin P, et al. High frequency of
coeliac disease in adult patients with type-I
diabetes. Scand J Gastroenterol 19892481.
54
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 gluten-free 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 1999117297. 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 2000137263.
55
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
1994351215-8. Collin P, Salmi J, Hallstrom O,
Reunala T, Pasternack A. Autoimmune thyroid
disorders and coeliac disease. Eur J Endocrinol
1994130137-40
56
Celiac Disease Other Autoimmune Endocrine
Disorders
In study of 605 controls and 422 patients (aged
1684 years) 30 of adult patients with CD had
at least one AI disease with an overall 23-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
200149502505
57
Celiac Disease Neuropsychologic Features
  • 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
58
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
59
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 199631013-9
60
Celiac Disease Other Associated Disorders
  • Aphthous stomatitis- unexplained oral ulcers have
    been reported as the sole presenting feature
  • Glossitis, angular stomatitis, and cheilosis have
    also been associated

61
Diagnosis of Celiac Disease
62
Diagnosis of Celiac Disease
  • Clinical Findings
  • Small Intestines Mucosal Biopsy
  • Gluten Re-challenge
  • Serologic testing

63
Diagnosis Small Bowel Endoscopy
Normal
Celiac
64
Diagnosis Small Bowel Endoscopy
65
Diagnosis Small Bowel Endoscopy
66
Histologic Findings of Celiac
Normal Jejunum
Celiac
Virginia Commonwealth Univ, Richmond, Virginia
Celiac Disease (Gluten-Induced Enteropathy)
65000-45800-F2923
67
Histologic Findings of Celiac
Normal
Flattened Villi in Celiac
68
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
69
Intestinal Lesions of Celiac Disease
Marsh, MN, Gastroenterology 1992 102330.
70
Histologic Findings of Celiac
Virginia Commonwealth Univ, Richmond, Virginia
Celiac Disease (Gluten-Induced Enteropathy)
65000-45800-F2923
71
Other Causes of Villous Atrophy
  • Bacterial Overgrowth
  • Crohns disease
  • Cows 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.
72
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 13432
73
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 65909.
74
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)

75
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 65909.
76
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 65909.
77
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 65909.
78
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 36743.
79
Diagnosis of Celiac IgA
  • IgA deficiency is more common in celiac disease
    (2 to 5 percent) than in the general population
    (lt0.5 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

80
Diagnosis of Celiac Disease
Probability lt 2 to 5 percent
Obtain IgA endomysial or tTG Ab and serum IgA
level
Positive
Negative
Small bowel biopsy
Diagnosis excluded
81
  • Family history
  • Unexplained iron deficiency anemia
  • Steatorrhea or other GI symptoms
  • Failure to thrive
  • Type 1 diabetes mellitus or other associated
    disorders
  • Other symptoms

Probability gt 2 to 5 percent
IgA endomysial or tTG Ab IgA AND Small bowel
biopsy
Histology - Serology
Histology Serology -
Both positive
Both negative
Rule out other causes of villous atrophy
-


Review and/or repeat biopsy
Diagnosis excluded
TREAT
-
82
Management of Celiac Disease
83
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 14279
84
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.

85
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 Fordtrans Gastrointestinal and
Liver Disease, 6th Ed, Feldman, M, Scharscmidt,
BF, Sleisenger, MH (Eds), Saunders, Philadelphia
1998. p. 1568
86
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

87
Taxonomy of Grains
Gliadins
Secalins
Hordeins
Avenins
Zeins
KAGNOFF, MF. Overview and Pathogenesis of Celiac
Disease GASTROENTEROLOGY 2005128S10S18
88
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 3331033
89
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
3927
90
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 521649. Thompson, T. Gluten contamination
of commercial oat products in the United States.
N Engl J Med 2004 3512021. Hoffenberg, EJ,
Haas, J, Drescher, A, et al. A trial of oats in
children with newly diagnosed celiac disease. J
Pediatr 2000 137361
91
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 2830, 2004
92
Management of Celiac Disease
N20
N10
Serum IgA antigliadin titers at diagnosis and
after 12 16 months of dietary therapy
93
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.
94
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 2830, 2004
95
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