Transcript Celiac talk - Downeast Celiacs.com

Moncton, May 27,
2007
F. Schweiger MD
Celiac sprue - Definiton
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Intolerance to gluten proteins from wheat
and to related proteins from barley or rye
Presents with characteristic
histopathological changes of the jejeunal
mucosa
Consequences: from asymptomatic to
global malabsorption and an increased
risk to develop GI malignancies
Manifestation by genetic,
environmental,and immunological factors
Mortality of celiac sprue
Before introduction of gluten-free diet:
544 children
12 %
Hardwick 1939
(malabsorption and infection)
After introduction of gluten-free diet
(Dickie 1951):
485 children
653 adults
335 adults on GFD
0.4 %
2 x increased
no increase
Sheldon 1969
Logan et al 1989
Collin et al 1994
Prevalence of Celiac Disease
USA / Canada
Irish
Italians with “dyspepsia”
Swedish blood donors
Brazilians
Baltimore (USA)
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1 in 100
1 in 152
1 in 103
1 in 256
1 in 680
1 in 300
Rare in Afro-Caribbean, Chinese, Japanese
Mild female preponderance (2:1 at most)
Triggers of celiac disease
Infectious (viral
Diatetic
bacterial)
(gluten)
Genetic
HLA-DQ2
Immune-maturation
Autoimmunity
Th2
Sprue
Th1
Gramineae
Family
Subfamily
Tribe
Festucoideae
Triticeae
Panicoideae
Aveneae Oryzeae
Subtribe Triticineae Hordeinae
Paniceae
Tripsacinae Anthrxoninae
Genus Triticum Secale Hordeum Avena Oryza
Wheat Rye Barley
Andropogoneae
Oats Rice
Zea
Sorghum Pennisetum
Corn Sorghum
Millet
Toxic wheat proteins
Glutelins (glutenins of wheat)
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Gluten
Soluble in acids and bases
45 % Glu
Prolamines (gliadins of wheat)
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Soluble in 50 – 70 % ethanol
30 – 56 % Glu, 15 – 30 % Pro
Alpha, beta, gamma, delta gliadins
Toxic peptides: PSQQ, QQQP
Environmental Factors
OATS
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Oats may be tolerated by patients
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Oats contain less QQQPF (toxic fraction in wheat
gliadin)
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Prolamines in oats have less glutamine and proline
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Tolerance to oats depends on the amount consumed
(less than 40 gm)
Genetic factors
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Concordance in monozygotic twins : 75 %
Risk to first degree relatives : 2 – 15 % (10 %)
Risk to 2nd degree relatives : 3 – 5 %
Familial clustering of celiac disease/dermatitis
herpetiformis
1.degree relatives
number
sprue/DH prevalence
Parents
Sisters/brothers
Offspring
2.degree relatives
521
368
54
54
22
51
7
3
4.2 %
13.8 %
12.9 %
5.6 %
Total
997
83
8.3 %
Relatives: Who and How to Screen ?
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Index case has proven celiac disease
Relative is interested in being screened
Relative is willing to undergo diagnostic testing
Relative is willing to undergo treatment
Relative will derive benefit from treatment
If relative is symptomatic, approach is diagnostic not
screening
S. Crowe, DDW 2007
Classical presentation of celiac disease
1960-ies, Helsinki, Finland
Number
Age at initial symptoms (months)
Duration of gluten ingestion (months)
Age at admission (months)
Diarrhea
Vomiting
Growth retardation
Weight below 2.5 percentile
Distended abdomen
53
7.7
4.3
10.2
87 %
74 %
98 %
70 %
64 %
Acta Ped Scand 1967
Celiac Disease in Adults
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20 % over age 60
Often mistaken for Irritable Bowel Syndrome
50 % do not have diarrhea
Iron deficiency anemia most common presentation
Unmasking by gastric surgery
May present as recurrent “canker sores”
Significant fatty stools uncommon
Abdominal pain uncommon
Atypical Presentations (1)
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Nonspecific
Weight loss, lethargy, fatigue
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Hematological
bruising (Vitamin K), anemia
(iron,folate ,B12)
hyposplenism (thrombocytosis)
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Neurological
cerebellar ataxia, peripheral
neuropathy,post/lateral column
abnormalities, neuromyopathies,
epilepsy (+/-cerebral calcifications)
demyelinating CNS lesions
Atypical Presentations (2)
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Musculoskeletal
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Gynecologic
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Dermatologic
Psychiatric
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Osteoporosis, osteomalacia, #s
osteoarthropathy,tetany,weakness
dental enamel hypoplasia,
primary or secondary amenorrhea
infertility, recurrent abortions
alopecia, follicular keratosis
depression, psychosis,
schizophrenia
Atypical Presentations (3)
Endocrine :
pubertal delay, short stature,
2nd hyperparathyroidism, infertility,
impotence, amenorrhea
Dietary Response -? Diagnostic
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Placebo response in IBS up to 70 %
Gluten (increased prolamines) is hard to digest
GFD often eliminates other dietary factors
Symptomatic response to GFD, especially a
transient response, does not imply the diagnosis
of celiac disease
Laboratory tests
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Protein:
Albumin, globulins, Liver tests
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Carbs :
glucose, Lactose-H breath test, (D-Xylose)
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Fats :
(stool for fat), lipid profile, carotene
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Minerals : Ca, Mg, P, Fe, ferritin,zinc
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Vitamins : RBC folate, B12, Vit A, 25-OH Vitamin D, PT
Serologic Tests for Celiac Disease
Serologic Test
Sensitivity
Specificity
percent
PPV
Anti-EMA (IgA)
85-98
97-100
IgA antigliadin
75-90
82-95
28-100 65-100
IgG antigliadin
69-85
73-90
20-95
tTg (IgA)
92-98
95-98
99
NPV
93
41- 88
Epidemiology of Celiac Disease
the sprue iceberg
EMA present
EMA present
Asymptomatic
Clinical
CD
Silent
CD
Abnormal
mucosa
Latent CD
Normal
Healthy
individuals
mucosa
The asymptomatic patient
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Reduction in risk of enteropathic T-cell lymphoma
Reversal of unrecognized nutritional deficiences
Resolution of mild or unrecognized symptoms
Avoidance of other autoimmune disorders
Improvement of general well-being
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Advantages of screening:
Disadvantages of screening:
Lack of motivation to adhere to GFD
Adverse psychological effects
Mass screening currently not advocated
Pathology of celiac disease
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Length of SB involvement correlates with clinical
severity
GFD results in marked improvement beginning
distally
Histology is not specific
Causes of villous atrophy
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Cow’s milk protein intolerance (children)
Post-gastroenteritis
Giardiasis
Peptic duodenitis (including ZES)
Crohn’s disease
Small intestinal bacterial overgrowth
Eosinophilic enteritis
Radiation or cytotoxic therapy
Tropical sprue
Severe malnutrition
Diffuse small intestinal lymphoma
Graft versus host disease
Hypogammaglobulinemia
Alpha chain disease
Prevalence (%)
Prevalence of autoimmune disease in celiac disease
40
35
30
25
20
15
10
5
0
<2
2 to 4
4 to 12
12 to 20
age at diagnosis of celiac sprue (years)
> 20
Celiac disease and associated disorders
Definite Association
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Dermatitis herpetiformis
Insulin-dependent Diabetes
Thyroid disease
IgA deficiency
Epilepsy with cerebral calcifications
Inflammatory bowel disease
Microscopic colitides
IgA mesangial nephropathy
Chronic autoimmune hepatitis
Sclerosing cholangitis
Primary biliary cirrhosis
Down syndrome (3-12%)
Turner syndrome
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Rheumatoid arthritis
Sarcoidosis
Bird fancier’s lung
Fibrosing alveolitis
Recurrent pericarditis
Idiopathic pulmonary
hemosiderosis
Dermatitis herpetiformis
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Papulovesicular lesions of extensor surfaces, buttocks,
trunk, neck and scalp
Intensely pruritic
Early or middle adult life; M = F
2/3 have patchy enteropathy; tends to be less severe
Less than 10 % have intestinal symptoms
10 – 40 fold increased risk of lymphoma
Dermatitis herpetiformis
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Frequency of Abs to tTG only about 75 %
More than 80 % of pts with DH have sprue
10 % of celiacs have DH
Tx: Dapsone 1 – 2 mg/kg (does not improve SB)
GFD allows most patients to reduce/stop Dapsone
Celiac disease and type 1 DM
Patients (n)
Finland
Finland
Italy
Italy
Italy
Sweden
Ireland
UK
Germ/Switz
Australia
USA
children (776)
adults (195)
children (498)
adults (383)
adults (639)
children (436)
adults (101)
adults (767)
children (1032)
children (273)
children (211)
Pos (%)
2.4
4.1
3.2
2.6
7.8
4.6
4.9
2.0
1.2
1.8
1.4
Celiac disease and Osteoporosis
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Prevalence of CD is increased in osteoporosis (1.5-3%)
Especially in premature osteoporosis/osteomalacia
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Newly diagnosed CD : spine 28 % & hip 15 %
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Patients with asymptomatic CD have increased risk
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Postmenopausal females are at greatest risk
Celiac disease and Osteoporosis
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Vitamin D deficiency is common in CD
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Bone mineral density increases with GFD, especially in
the first year of treatment
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Axial bone mass increases more then appendicular BMD
Celiac disease and Osteoporosis
Adequate calcium and vitamin D intake
 Regular weight bearing exercises
 Smoking cessation; avoid alcohol
 Correction of hypogonadism
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Celiac Disease and Osteoporosis
Baseline DEXA at dignosis or initial assessment
T < -2.5
-2.5< T < -1.0
T > -1.0
Treat with bisphosphonates
Calcium / Vitamin D ***
Lifestyle measures alone ***
Repeat DEXA every 12 months
Repeat DEXA every 12 months
Repeat DEXA evey 24 months
Celiac disease and associated conditions
Possible association
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Congenital heart disease
Lung cavities
Sjogren’s syndrome
Systemic and cutaneous
vasculitis
SLE
Polymyositis
Schizophrenia
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Myasthenia gravis
Iridocyclitis or choroiditis
Cystic fibrosis
Macroamylasemia
Addison’s disease
Autoimmune
thrombocytopenic purpura
Autoimmune hemolytic
anemia
Celiac Disease and Malignancies
44/105 deaths during 13.5 years in 653 (untreated) patients from
Edinburgh, Scotland
Risk
All malignancies
Lymphoma
Intestinal carcinoma
Esophageal carcinoma
3x
30 x
3x
8x
Logan et al, Gastroenterology 1989
Cancer and Celiac Disease
12, 000 celiac patients in Sweden over 30 years:
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6-fold increased risk of lymphoma (18% of all Ca)
Oropharyngeal Ca (SCC)
Esophageal Ca (SCC)
Small bowel Ca
Colon Ca - confined to subjects older than 60
Primary liver Ca
Reduced occurrence of breast Ca
Askling et al. Gastro 2002
Celiac Disease and cancer
Strict adherence to a GFD probably reduces the risk
of enteropathy-associated T cell lymphoma as well
as the other malignancies
Treatment of Celiac Disease
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Dietary counseling and strict avoidance of gluten
Initial avoidance of dairy products
Replacements of micronutrients in case of deficiencies
Corticosteroids/azathioprine for celiac crisis or refractory
sprue
Treatment of Celiac Disease
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Non-compliance is an issue - eating out of home
- peer pressure for children
- less acceptable taste
- accidental ingestion of G.
- cost, availability, labelling
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Use of oats, wheat starch controversial
GFD reduces risk of malignancy
Unclear how much gluten if any is safe
- new FDA guidelines up to 10 mg/day safe ?
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S. Crowe, DDW 2007
Response to Treatment
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Clinical improvement in 2 weeks in 70 %, by 6 weeks in
most
Serological improvement by 4 – 6 weeks
Histological improvement in up to 2 years
Gaining weight above ideal BMI
Constipation
Falling off the diet and getting ill again
S. Crowe, DDW 2007
Patient on GFD – no Biopsy!
Celiac disease is possible and patient
willing to undergo a gluten challenge
YES, ideally get
genetic testing
NO, but wants
genetic testing
no further testing if
wants to stay on GFD
regardless of testing
Challenge if DQ2 or DQ8
Positive; check Abs q 2 m
EGD + Bx, if Ab +ve,
Symptoms develop or
By 6 months
+ve, increases
-ve – not celiac dis.
likelyhood of CD
? Use GFD for
suggest G challenge symptom control only
S.Crowe, DDW 2007
Gluten Challenge
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Gradual increase of gluten in diet up to target (typically 4
slices of bread/day)
Check tTG at 4-6 weeks and at intervals thereafter until
positive
Biopsy if diarrhea develops and/or become seropositive
Management if sero-negative at 3-6 months needs to be
individualized
S.Crowe, DDW 2007
Treatment of celiac disease
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Histology may not recover completely despite clinical
normalization
Negativation of IgA anti-TTG after 4 – 6 months of a
strictly gluten-free diet (GFD)
Diagnosis to be reconsidered when no clinical
improvement is reached after 6 – 9 months of a GFD
Risk of malignancy approaches baseline after 5 years of
a GFD
Why a Gluten Free Diet ?
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Benefits overall cancer risk
Improves unexplained infertility
Improves osteoporosis
Corrects iron deficiency
Improved QOL even for those detected by screening
GFD is beneficial for preventing, reversing and/or
treating some complications
Summary
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Celiac disease is not rare (1 in 100-300)
It can present in many ways
iron deficiency anemia, depression, osteoporosis, abnormal liver tests, nonspecific or IBS-like symptoms, dyspepsia, DH, recurrent miscarriages,
microscopic colitis
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Associated with autoimmune diseases
Screening with tTG IgA is best
Confirm diagnosis with duodenal biopsy
Cornerstone of treatment is avoidance of gluten
?