celiac disease - arup.utah.edu disease final 19.8.12.pdfaug 12, 2019 · chronic diarrhea ≥3...
TRANSCRIPT
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CELIAC DISEASE Jolanta Jedrzkiewicz, MD, 10.15.12
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University of Utah CME Statement 2
The University of Utah School of Medicine adheres to ACCME Standards regarding industry support of continuing medical education.
Speakers are also expected to openly disclose intent to discuss any off-label, experimental, or investigational use of drugs, devices, or equipment in their presentations.
This speaker has nothing to disclose.
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9 month old boy with failure to thrive 3
On questioning: 3 months ago, solid foods were introduced to his diet
including cereal
Physical exam: Dehydrated, irritable, has a distended abdomen and
has not gain weight since the last visit (a month ago)
Family history: Both parents have celiac disease
Diagnosis: CELIAC DISEASE Treatment: Gluten free diet
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Celiac disease (CD) 4
Definition: Inflammatory disease of the gut that occurs in
predisposed individuals after gluten (wheat) ingestion.
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CME objectives 5
List the symptoms of celiac disease Identify the agent that causes celiac disease List criteria for diagnosis Compare and contrast different tests that are used Justify utilization of serology (antibody test) List the antibodies that we test for Justify utilization of HLA testing List the HLA tests that are used in assessing the risk Describe current guidelines and recommendations
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Topics 6
Definitions and historical background Clinical symptoms Histologic changes in celiac disease Pathophysiology Serologic tests HLA testing Screening Treatment Monitoring adherence to treatment Cases
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Why celiac disease? 7
1% in the U.S. 5% prevalence in type 1 DM patients 10% higher prevalence in first degree relatives 70% concordance in identical twins
Population affected: Age: infancy, 20-30s, 50-60s Historically, Caucasians of North European ancestry
Consequences for untreated patients Malabsorption Cancer
Henry’s textbook, edition 22
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Historical background
100-200 AD: Aretaeus (Greek physician) Description of disease
1888: Gee Dietary causation
1950s: Dicke and colleagues Wheat and rye brought on celiac disease
1954: Paulley Clinical manifestation are linked to small intestine damage
1990s: genetic association with HLA 1992: Marsh
Histologic classification
8
Abadie, 2011
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Prevalence of celiac disease 9
Abadie, 2011
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Wheat consumption 10
Abadie, 2011
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11
Interactions between celiac disease (CD)–associated genes and key immunological markers of CD.
Abadie, 2011
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12
Celiac disease
Genetics
Immunity Environment
Multifactorial disease
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Clinical manifestation
Intermittent diarrhea Abdominal pain Bloating
Irritability or depression Stomach upset Joint pain Muscle cramps Anemia Osteoporosis Neuropathy Skin rash Mouth sores
13
http://fe.blog.images.s3.amazonaws.com/2010/04/celiac_iceberg.jpg
Malabsorption, common
Dermatitis herpetiformis
Nonspecific
Henry’s textbook, edition 22
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Abdominal symptoms
Villous atrophy/ damage
Chronic diarrhea ≥3 watery or loose bowel
movements in a 24h ≥ 4 weeks Osmotic type
Water to be pulled into the gut
Steatorrhea (diarrhea with high fat content)
Abdominal bloating Abdominal pain
0%
1%
2%
3%
4%
5%
Chronic diarrheaprevalence
TotalCDOther
14
Malabsorption
Up-to-date. “Approach to the adult with chronic diarrhea in developed countries” Last updated on Jun 7,2011
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Malabsorption
Total malabsorption Vitamins Minerals Proteins Fats
15
Anemia
Neuropathy
Osteoporosis
Weight loss & weakness
Steatorrhea
Ca, P, Fe, vit A B D E K, Folate
stomach
duodenum
ileum
large bowel
jejunum
Lipids, sugar, amino acids, small peptide
Vit C B(12) D K
Water vit K and biotin
Evaluation of Chronic Diarrhea GREGORY JUCKETT and RUPAL TRIVEDI
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Imaging Normal villi
Atrophic villi, celiac disease
Normal villi
Atrophic villi, celiac disease
Spada et al, 2008
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A. Scalloping
B. Mosaic pattern
C. Micro-nodularity
D. Reduction of folds
Spada et al, 2008
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18
Normal histology, Low power
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19
Normal histology, High power
Enterocytes
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Comparing normal and abnormal 20
Normal histology, long villi Abnormal histology, short and bland (atrophic) villi, celiac disease
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Microscopic findings in CD
Intraepithelial lymphocytes
Increase in plasma cells in lamina propria
Atrophy or total loss of villi
Fat globules in surface epithelium
Enterocytes have stratified nuclei
Crypt hyperplasia
21
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Modified Marsh classification used in CD histologic grading
22
Duodenal and jejunal biopsy – gold standard for CD diagnosis Marsh 0-1
Consider early phase disease Follow-up testing on normal diet Consider false-positive results
Marsh ≥2 Celiac disease confirmed
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Skin manifestation 23
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Dermatitis herpetiformis
Pruritic vesicles Symmetric
Extensor surfaces Rare mucous membrane
involvement Microscopy
Subepidermal blisters Neutrophilic
microabcesses in papillary dermal tips
Lymphocytic infiltrate around superficial vascular plexus
24
Epidermis
Junction
Dermis
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Dermatitis herpetiformis
Incidence – 10-39/100,000 Age – all ages; peak onset
is 20s-40s Most common autoimmune
bullous disease of childhood Strong association with HLA-
DQ2 Diagnostic: granular IgA and
C3 in papillary dermal tips Treatment: gluten free diet,
dapsone or sulfapyridine
25
Epidermis
Junction
Dermis
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Pathophysiology
What is Gluten? 26
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WHAT IS GLUTEN?
PROLAMINS 15% proline and
35% glutamine
27
PROTEIN
Shewry et al, 2002
http://injust10pages.com/blog/gluten_intolerance_blog?page=2
Gluten - 75% and remainder being starch and lipids
Storage Elasticity and
extensibility
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GLUTEN composition 28
Peptides similar to gliadin are in Rye and Barley
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29
Gliadin
Partial proteolysis
Gliadin
Gluten
AA AA AA
Digestion Tietz textbook, 5th edition
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Pathophysiology 30
Enterocyte
Enterocyte
Enterocyte
Lumen of gut
Absorptive epithelium Gliadin
Gliadin
Tietz textbook, 5th edition
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Pathophysiology 31
Enterocyte
Enterocyte
Enterocyte
Lumen of gut
Absorptive epithelium Gliadin
Tietz textbook, 5th edition
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Pathophysiology 32
Enterocyte
Enterocyte
Enterocyte
Lumen of gut
Absorptive epithelium Gliadin
Gliadin
Tietz textbook, 5th edition
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Pathophysiology 33
Enterocyte
Enterocyte
Enterocyte
tTG
Lumen of gut
Absorptive epithelium Gliadin
Gliadin
Tietz textbook, 5th edition
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Pathophysiology 34
Enterocyte
Enterocyte Gliadin
Enterocyte
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 35
Enterocyte
Enterocyte Gliadin
Enterocyte
APC
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 36
Enterocyte
Enterocyte
Enterocyte
APC
Gliadin
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Sensitization in duodenum 37
Enterocyte
Enterocyte
Enterocyte
APC Gliadin
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 38
Enterocyte
Enterocyte
Enterocyte
HLA
Gliadin
APC
HLA DQ2 HLA DQ8
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 39
Enterocyte
Enterocyte
Enterocyte
HLA
APC
Gliadin
Naïve T cell
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 40
Enterocyte
Enterocyte
Enterocyte
HLA
Gliadin
APC
Naïve T cell
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 41
Enterocyte
Enterocyte
Enterocyte
HLA
Gliadin
APC
Gluten specific Th cell
Lumen of gut
Absorptive epithelium Gliadin
tTG
Tietz textbook, 5th edition
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Pathophysiology 42
Enterocyte
Enterocyte
Enterocyte
Plasma cell
Y Y Y INFy
TNFa
Th cell interacts with cytotoxic cells to facilitated cellular damage via release of INFy and TNFa.
Th cell interacts with B cell to stimulate plasma cells that produce anti-gluten antibodies.
Lumen of gut
Absorptive epithelium Gliadin
Gluten specific Th cell
Tietz textbook, 5th edition
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Pathophysiology 43
Enterocyte
Enterocyte
Enterocyte
Plasma cell
Y Y INFy
TNFa
Y
The number of intraepithelial lymphocytes increase.
The number of plasma cells in lamina propria increase.
Gluten specific Th cell
Plasma cell
Plasma cell
Plasma cell
Lumen of gut
Absorptive epithelium Gliadin
Th cell interacts with cytotoxic cells to facilitated cellular damage via release of INFy and TNFa.
Tietz textbook, 5th edition
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Selective IgA immunodeficiency 44
Plasma cell
Selective IgA immunodeficiency The most common primary
immunodeficiency 1 in 223-1000
Serum IgA level of less than 5-10 mg/dL
Recurrent infections and bronchiectasis Allergy Increased risk of developing atopic or
autoimmune disease Including celiac disease Y
Y Y
Emami et al. 2005
IgA
IgG
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Serologic tests for antibodies 45
IFA
ELISA
Endomysial Antibody, IgA and IgG (EMA)
Reticulin Antibody, IgA and IgG
Tissue Transglutaminase IgA and IgG (tTG)
Deamidated Gliadin Peptide IgA and IgG (DGP)
F-Actin (Smooth Muscle) Antibody, IgA
Anti-gliadin antibodies (AGA)
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Endomysial Antibody (EMA) 46
Identified antigen for EMA Endomysial Antibody Endomysial component of
smooth muscle layers or connective tissue stroma covering individual muscle fibers
Intracellular tissue transglutaminase (tTG)
Dieterich et al. 1997
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Endomysial Antibody (EMA)
Labor intensive Reading errors
Expensive May be used for
confirmation if anti-tTG is equivocal Very specific* Acceptable screen High positive predictive
value for active CD
47
Salmi et al, 2006
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Reticulin Antibody, IgA and IgG 48
IgG class reticulin antibodies bullous dermatoses and other diseases, and sometimes in normal patients Reticulin is a type of fiber composed of type III
collagen
Not recommended for CD testing IgA 25% dermatitis herpetiformis IgA 60% celiac disease
Stevens et al, 1975
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Indirect Fluorescent Antibody (IFA)
Methodology 49
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Indirect Fluorescent Antibody (IFA) 50
Monkey esophageal tissue
Y
Y
Y
serum
Y
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Indirect Fluorescent Antibody (IFA) 51
Monkey esophageal tissue
Y
Y
Y
Y
Wash
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Indirect Fluorescent Antibody (IFA) 52
Monkey esophageal tissue
Y
Y
Y
Y
Y
Y Y Y
Fluorescein-labeled Antibodies (FITC)
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Indirect Fluorescent Antibody (IFA) 53
Monkey esophageal tissue
Y
Y
Y
Y
Fluorescein-labeled Antibodies (FITC)
Y
Y
Y
Y
Wash
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Indirect Fluorescent Antibody (IFA) 54
Monkey esophageal tissue
Y
Y
Y
Y
Fluorescein-labeled Antibodies (FITC)
Y
Y
Y
Y
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55
Immunofluorescence
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DGP, tTG and AGA antibodies 56
DGP and tTG are used in screening population at risk or with symptoms
DGP IgG antibodies more sensitive but less specific markers for disease compared with IgA class antibodies
Anti-gliadin antibody (AGA) can be found in healthy individuals or in other bowel diseases No longer a recommended test
tTG antibody may be less reliable in children
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F-Actin (Smooth Muscle) Antibody
Adjunct test Monitoring tool for
patients with severe disease Correlate with severity
Test results alone are not diagnostic
57
Carroccio et al, 2007
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Enzyme linked immunosorbent assay (ELISA)
Methodology 58
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Enzyme linked immunosorbent assay (ELISA)
Y Y
Epitope of interest fixed to the well
Patient’s serum
Y Y
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Enzyme linked immunosorbent assay (ELISA)
Y Y
Epitope of interest fixed to the well
Patient’s serum
Y Y Y Y Y Y
Horseradish peroxidase (HRP)-labeled Ab
Incubate and wash
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Enzyme linked immunosorbent assay (ELISA)
Y Y
Epitope of interest fixed to the well
Patient’s serum
Y Y Y Y Y Y
Horseradish peroxidase (HRP)-labeled Ab
Tetramethylbenzidine (TMB)
TMB TMB
TMB TMB
Incubate and wash
Incubate and wash
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Enzyme linked immunosorbent assay (ELISA)
Y Y Y Y Y Y Y Y
TMB TMB
TMB TMB
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Summary for serological tests Tietz textbook, 5th edition
IgA Method Sensitivity Specificity
tTG ELISA >90% >99%
DGP ELISA >90% >90%
EMA IFA 80-100% >99%
reticulin Ab* IFA 24-30% >90%
gliadin ELISA 75-95% >95%
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Diagnosis of celiac disease 64
1 •Clinical manifestations
2 •Antibody/ serology
3 •HLA test
4 •Biopsy
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Major histocompatibility complex (Human leukocyte antigen - HLA)
65
CLASS II HLA CLASS I HLA
Chromosome 6
D D D A C B R Q P
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HLA-DQ as heterodimeric (αβ) receptor
66
Paternal
Maternal
HLA-DQB1 HLA-DQA1
APC
β α
There are many slightly different α and β
β α
β α
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Everybody has 2 HLA-DQ genes 67
Paternal
Maternal α
β
α
β
APC
β
β
α β
α
α
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Haplotype 68
Definition: Combination of alleles of DNA sequences at adjacent locations on the chromosome that are transmitted together
CLASS II HLA
D D R Q
Haplotype
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Haplotype 69
CLASS II HLA
D D R Q
α05 01
β02 01
DR3
2
DQ2.5
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Haplotype 70
Haplotype DR3-DQ2 The most common haplotype associated with celiac
disease European prevalence up to 21.9 % African prevalence of up to 17.3 % Rare in Asian and Native Americans population
D D R Q
α05 01
β02 01
DR3
2
DQ2.5
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Frequency of HLA DR3-DQ2 71
Abadie, 2011
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Trans vs. cis alleles in DQ2 72
α05 01
β02 01
DR3
β
β02 02
α05 05
α
DR5
DR7
trans
cis
α05 01
β02 01
DR3
Allele 1, DQ2.5
Allele 2, DQ2.5
Allele 2
Allele 1
cis
2x
DQ2.2 1x
Dosage If patient has two alleles both encoding DQ2 (homozygous), the risk ↑↑↑
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HLA-DQ 2 and 8 predispose for CD 73
α05 01
β02 01
DR3
β
β02 02
α05 05
α
α03
α02 01
β02 02
β03 02
DR5
DR7
DR7
DR4
trans
cis
cis
cis
DQ2
DQ2
DQ2
DQ8
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PCR with SYBR Green I technique
Methodology 74
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PCR 75
Polymerase Primers: DQB1*02 DQA1*05 DQB1*03:02 Patient’s DNA
Fluorescence is increases upon binding to double-stranded DNA
Signal ↑ as the DNA concentration ↑
Melting analysis
SYBR Green I technique/ fluorescent DNA binding dye
DQ2
DQ8
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HLA summary 76
HLA-DQ2 is positive in 90-95% of patients with CD Presence does not confirm CD Found in 30-40% of general population Absence virtually excludes CD May be indicated in individuals at risk for CD or individuals
who are repeatedly seropositive but biopsy-negative Results HLA positive (and other serology/ clinical history +) – CD
confirmed Not necessary to confirm by biopsy HLA negative – likely false-positive tTG test
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Screening for celiac disease 77
Not recommended for the general population DGP and tTG IgA and IgG Utility of HLA tests:
Type 1 DM, Autoimmune thyroid disease, IBS, Dermatitis herpetiformis, Selective IgA deficiency Absence of DQ2 and DQ8 render CD highly unlikely
Equivocal biopsy
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Treatment of celiac disease 78
Gluten-free diet (GFD)
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Foods containing gluten 79
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Gluten-free foods 80
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Monitoring adherence to treatment 81
Monitoring adherence to gluten-free diet (GFD) or disease activity is part of American Gastroenterological Association (AGA) guidelines tTG and/or DGP IgA and IgG assays Typically ordered every 3-6 months If high for >12 months consider rebiopsy
F-actin IgA antibody Declining levels of F-actin IgA
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Cases and questions 82
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22 yo F with weakness and fatigue when exercising
83
Upon further questioning Tingling and numbness in her fingers Itchy rash Diarrhea for past 2 years with
associated abdominal pain
Serology was done IgA WNL
DGP IgA high tTG IgA high
HLA typing DQ2 positive
Diagnosis: Celiac disease
What is the treatment?
Gluten free diet
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Conclusion 84
Gluten free diet is treatment of celiac disease
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60 yo M w/ diarrhea 85
Upon questioning Diarrhea started yesterday after
he ingested a very old potato salad
On exam scaly rash was observed (upon questioning he first noticed the rash 10 years)
Should tTG and DGP be done in this case? No
This patient has probably psoriasis and ingested potato salad with Staph aureus toxin.
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Conclusion 86
Chronic diarrhea is a symptom of celiac disease
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31 yo M with allergies, weakness and diarrhea
87
Diarrhea for past 3 years Patient has been losing weight for past 2 years IgA screen was performed
IgA - not detected What immunoglobulin should be tested in this patient?
DGP and tTG IgG Results came back negative, what now?
HLA testing/biopsy Patient is HLA DQ2 and DQ8 positive Biopsy showed short villi
Celiac disease was diagnosed
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Conclusions 88
If patient has selective IgA immunodeficiency, use IgG in serologic tests
HLA DQ2 and DQ8 predispose for CD Patient with CD will show short villi on biopsy
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Which of the following foods contains gluten?
89
A. Orange juice B. Honey C. Whiskey D. Seaweed E. None of the above
Whiskey is a type of distilled alcoholic beverage made from fermented grain mash.
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Acknowledgment 90
Dr. Tebo Dr. Delgado Dr. Rockwood ARUP University of Utah
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Thank you 91
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Questions? 92
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References
ARUP consult ARUP directory Master control Henry’s textbook Tietz textbook Pubmed
93