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Celiac Disease. Moncton, May 27, 2007. F. Schweiger MD. 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

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slide1

Celiac Disease

Moncton, May 27, 2007

F. Schweiger MD

celiac sprue definiton
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
mortality of celiac sprue
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

prevalence of celiac disease
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 (2:1 at most)
triggers of celiac disease
Triggers of celiac disease

Infectious (viral

bacterial)

Diatetic

(gluten)

Genetic

HLA-DQ2

Autoimmunity

Immune-maturation

Th2 Th1

Sprue

slide6
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

toxic wheat proteins
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

environmental factors oats
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)
genetic factors
Genetic factors
  • 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
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 %

relatives who and how to screen
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

classical presentation of celiac disease 1960 ies helsinki finland
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

celiac disease in adults
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
atypical presentations 1
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

atypical presentations 2
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

atypical presentations 3
Atypical Presentations (3)

Endocrine : pubertal delay, short stature,

2nd hyperparathyroidism, infertility,

impotence, amenorrhea

dietary response diagnostic
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
laboratory tests
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
serologic tests for celiac disease
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

epidemiology of celiac disease the sprue iceberg
Epidemiology of Celiac Diseasethe sprue iceberg

Clinical CD

Abnormal

mucosa

Silent CD

EMA present

EMA present

Asymptomatic

Latent CD

Normal

mucosa

Healthy individuals

the asymptomatic patient
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

pathology of celiac disease
Pathology of celiac disease
  • Length of SB involvement correlates with clinical severity
  • GFD results in marked improvement beginning distally
  • Histology is not specific
causes of villous atrophy
Causes of villous atrophy
  • 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
celiac disease and associated disorders definite 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 fancier’s lung

Fibrosing alveolitis

Recurrent pericarditis

Idiopathic pulmonary hemosiderosis

Celiac disease and associated disordersDefinite Association
dermatitis herpetiformis
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
dermatitis herpetiformis1
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
celiac disease and type 1 dm
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

celiac disease and osteoporosis
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
celiac disease and osteoporosis1
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
celiac disease and osteoporosis2
Celiac disease and Osteoporosis
  • Adequate calcium and vitamin D intake
  • Regular weight bearing exercises
  • Smoking cessation; avoid alcohol
  • Correction of hypogonadism
celiac disease and associated conditions possible association
Congenital heart disease

Lung cavities

Sjogren’s syndrome

Systemic and cutaneous vasculitis

SLE

Polymyositis

Schizophrenia

Myasthenia gravis

Iridocyclitis or choroiditis

Cystic fibrosis

Macroamylasemia

Addison’s disease

Autoimmune thrombocytopenic purpura

Autoimmune hemolytic anemia

Celiac disease and associated conditionsPossible association
celiac disease and malignancies
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

cancer and celiac disease
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

celiac disease and cancer
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
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
treatment of celiac disease1
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

response to treatment
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

patient on gfd no biopsy
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

gluten challenge
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

treatment of celiac disease2
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
why a gluten free diet
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

summary
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