Celiac talk

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Celiac Disease
Moncton, May 27, 2007
F. Schweiger MD
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Celiac sprue - Definiton

• 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

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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 0.4
  Sheldon 1969
• 653 adults 2 x increased
  Logan et al 1989
• 335 adults on GFD no increase
  Collin et al 1994

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Prevalence of Celiac Disease

• USA / Canada 1 in
  100
• Irish
  1 in 152
• Italians with dyspepsia 1 in 103
• Swedish blood donors 1 in 256
• Brazilians 1
  in 680
• Baltimore (USA) 1 in 300
• Rare in Afro-Caribbean, Chinese, Japanese
• Mild female preponderance (21 at most)

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Triggers of celiac disease
Infectious (viral bacterial)
Diatetic (gluten)
Genetic HLA-DQ2
Autoimmunity
Immune-maturation Th2 Th1
Sprue
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• Family Gramineae
• Subfamily Festucoideae
  Panicoideae
• Tribe Triticeae Aveneae
  Oryzeae Andropogoneae Paniceae
• Subtribe Triticineae Hordeinae
  Tripsacinae Anthrxoninae
• Genus Triticum Secale Hordeum Avena Oryza
  Zea Sorghum Pennisetum
• Wheat Rye Barley Oats Rice
  Corn Sorghum Millet

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Toxic wheat proteins

• Glutelins (glutenins of wheat)
• Soluble in acids and bases
• 45 Glu
• Prolamines (gliadins of wheat)
• Soluble in 50 70 ethanol
• 30 56 Glu, 15 30 Pro
• Alpha, beta, gamma, delta gliadins
• Toxic peptides PSQQ, QQQP

Gluten
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Environmental FactorsOATS

• Oats may be tolerated by patients
• Oats contain less QQQPF (toxic fraction in wheat
  gliadin)
• Prolamines in oats have less glutamine and
  proline
• Tolerance to oats depends on the amount consumed
  (less than 40 gm)

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Genetic factors

• Concordance in monozygotic twins 75
• Risk to first degree relatives 2 15 (10 )
• Risk to 2nd degree relatives 3 5

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Familial clustering of celiac disease/dermatitis
herpetiformis

• 1.degree relatives number sprue/DH
  prevalence
• Parents 521
  22 4.2
• Sisters/brothers 368 51
  13.8
• Offspring 54
  7 12.9
• 2.degree relatives 54 3
  5.6
• Total 997
  83 8.3

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Relatives Who and How to Screen ?

• 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
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Classical presentation of celiac
disease1960-ies, Helsinki, Finland

• Number
  53
• Age at initial symptoms (months)
  7.7
• Duration of gluten ingestion (months)
  4.3
• Age at admission (months)
  10.2
• Diarrhea
  87
• Vomiting
  74
• Growth retardation
  98
• Weight below 2.5 percentile
  70
• Distended abdomen
  64

Acta Ped Scand 1967
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Celiac Disease in Adults

• 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

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Atypical Presentations (1)

• Nonspecific Weight loss, lethargy,
  fatigue
• Hematological bruising (Vitamin K), anemia
• (iron,folate
  ,B12)
• hyposplenism
  (thrombocytosis)
• Neurological cerebellar ataxia,
  peripheral
• 
  neuropathy,post/lateral column
• 
  abnormalities, neuromyopathies,
• epilepsy
  (/-cerebral calcifications)
• demyelinating CNS
  lesions

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Atypical Presentations (2)

• Musculoskeletal Osteoporosis, osteomalacia, s
• 
  osteoarthropathy,tetany,weakness
• dental enamel
  hypoplasia,
• Gynecologic primary or secondary
  amenorrhea
• infertility,
  recurrent abortions
• Dermatologic alopecia, follicular
  keratosis
• Psychiatric depression, psychosis,
• schizophrenia

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Atypical Presentations (3)

• Endocrine pubertal delay, short
  stature,
• 2nd
  hyperparathyroidism, infertility,
• impotence,
  amenorrhea

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Dietary Response -? Diagnostic

• 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

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Laboratory tests

• Protein Albumin, globulins, Liver tests
• Carbs glucose, Lactose-H breath test,
  (D-Xylose)
• Fats (stool for fat), lipid profile,
  carotene
• Minerals Ca, Mg, P, Fe, ferritin,zinc
• Vitamins RBC folate, B12, Vit A, 25-OH
  Vitamin D, PT

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Serologic Tests for Celiac Disease

• Serologic Test Sensitivity
  Specificity PPV NPV
• 
  percent
• Anti-EMA (IgA) 85-98
  97-100 99 93
• IgA antigliadin 75-90
  82-95 28-100 65-100
• IgG antigliadin 69-85
  73-90 20-95 41- 88
• tTg (IgA) 92-98
  95-98

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Epidemiology of Celiac Diseasethe sprue iceberg
Clinical CD
Abnormal mucosa
Silent CD
EMA present
EMA present Asymptomatic
Latent CD
Normal mucosa
Healthy individuals
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The asymptomatic patient

• Advantages of screening
• 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
• Disadvantages of screening
• Lack of motivation to adhere to GFD
• Adverse psychological effects
• Mass screening currently not advocated

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Pathology of celiac disease

• Length of SB involvement correlates with clinical
  severity
• GFD results in marked improvement beginning
  distally
• Histology is not specific

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Causes of villous atrophy

• Cows milk protein intolerance (children)
• Post-gastroenteritis
• Giardiasis
• Peptic duodenitis (including ZES)
• Crohns 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

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Prevalence of autoimmune disease in celiac disease
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Celiac disease and associated disordersDefinite
Association

• 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

• Rheumatoid arthritis
• Sarcoidosis
• Bird fanciers lung
• Fibrosing alveolitis
• Recurrent pericarditis
• Idiopathic pulmonary hemosiderosis

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Dermatitis herpetiformis

• 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

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Dermatitis herpetiformis

• 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

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Celiac disease and type 1 DM

• Patients (n)
  Pos ()
• Finland children
  (776) 2.4
• Finland adults (195)
  4.1
• Italy children
  (498) 3.2
• Italy adults
  (383) 2.6
• Italy adults
  (639) 7.8
• Sweden children (436)
  4.6
• Ireland adults (101)
  4.9
• UK adults
  (767) 2.0
• Germ/Switz children (1032)
  1.2
• Australia children
  (273) 1.8
• USA children
  (211) 1.4

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Celiac disease and Osteoporosis

• Prevalence of CD is increased in osteoporosis
  (1.5-3) Especially in premature
  osteoporosis/osteomalacia
• Newly diagnosed CD spine 28 hip 15
• Patients with asymptomatic CD have increased risk
• Postmenopausal females are at greatest risk

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Celiac disease and Osteoporosis

• Vitamin D deficiency is common in CD
• Bone mineral density increases with GFD,
  especially in the first year of treatment
• Axial bone mass increases more then appendicular
  BMD

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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
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Celiac disease and associated conditionsPossible
association

• Congenital heart disease
• Lung cavities
• Sjogrens syndrome
• Systemic and cutaneous vasculitis
• SLE
• Polymyositis
• Schizophrenia

• Myasthenia gravis
• Iridocyclitis or choroiditis
• Cystic fibrosis
• Macroamylasemia
• Addisons disease
• Autoimmune thrombocytopenic purpura
• Autoimmune hemolytic anemia

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Celiac Disease and Malignancies

• 44/105 deaths during 13.5 years in 653
  (untreated) patients from Edinburgh, Scotland
• 
  Risk
• All malignancies 3 x
• Lymphoma 30 x
• Intestinal carcinoma 3 x
• Esophageal carcinoma 8 x

Logan et al, Gastroenterology 1989
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Cancer and Celiac Disease

• 12, 000 celiac patients in Sweden over 30 years
• 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

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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

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Treatment of Celiac Disease

• 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

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Treatment of Celiac Disease

• Non-compliance is an issue - eating out of home
• 
  - peer pressure for children
• 
  - less acceptable taste
• 
  - accidental ingestion of G.
• 
  - cost, availability, labelling
• 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 ?
  
• 
  S. Crowe, DDW
  2007

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Response to Treatment

• 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

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Patient on GFD no Biopsy!

• Celiac disease is
  possible and patient
• willing to undergo
  a gluten challenge
• YES, ideally get NO, but wants
  no further testing if
• genetic testing genetic
  testing wants to stay on GFD
• 
  regardless of
  testing
• Challenge if DQ2 or DQ8
• Positive check Abs q 2 m
• EGD Bx, if Ab ve, ve, increases
  -ve not celiac dis.
• Symptoms develop or likelyhood of CD
  ? Use GFD for
• By 6 months suggest G
  challenge symptom control only

S.Crowe, DDW 2007
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Gluten Challenge

• 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
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Treatment of celiac disease

• 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

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Why a Gluten Free Diet ?

• 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

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Summary

• Celiac disease is not rare (1 in 100-300)
• It can present in many ways
• iron deficiency anemia, depression,
  osteoporosis, abnormal liver tests, non-specific
  or IBS-like symptoms, dyspepsia, DH, recurrent
  miscarriages, microscopic colitis
• Associated with autoimmune diseases
• Screening with tTG IgA is best
• Confirm diagnosis with duodenal biopsy
• Cornerstone of treatment is avoidance of gluten

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