Coeliac Disease: Diagnosis

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Coeliac DiseaseDiagnosis Management

• Dr Sameer Zar MBBS MRCP PhD
• Epsom St Helier NHS Trust

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Coeliac Disease

• Celiac disease (also known as gluten-sensitive
  enteropathy or nontropical sprue) is an
  immune-mediated inflammation of the small
  intestine caused by sensitivity to dietary gluten
  and related proteins in genetically sensitive
  individuals.
• The grains that contain the triggering proteins
  are wheat, barley, and rye there is some
  controversy as to whether oats also can cause the
  disease

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Factors to Consider in the Diagnosis of Coeliac
Disease

• Prevalence of disease
• Who is susceptible to developing the disease?
• Limitations of diagnostic tests
• Risks of coeliac disease and delayed diagnosis
• Benefits of treatment of disease
• What leads to over or under diagnosis?

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Prevalence of coeliac Disease

• Traditionally, highest prevalence was in western
  Ireland (1300) with lower values in other
  European countries (11000), and the USA
  (15000)
• Use of screening tests indicate a higher
  prevalence with values of 1100 - 1300 in most
  genetically susceptible populations
• However, it is estimated that less than 10-15 of
  current cases of coeliac disease are diagnosed

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Elevated Risk of coeliac Disease

• 1st and 2nd degree relatives
• Downs syndrome (12)
• Type I DM (3-8)
• Autoimmune thyroid disease (5)
• Symptomatic iron deficiency anaemia (10-15)
• Asymptomatic iron deficiency anaemia (3-6)
• Microscopic colitis (15-27)
• IBS (3-5)
• Chronic fatigue syndrome (2)
• Osteoporosis (1-3)

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Who develops coeliac Disease?Genetic and other
Factors

• 70 concordance in twins
• 10-15 prevalence in first degree relatives
• Other factors involved since most with these
  haplotypes do not get coeliac disease
• Other genetic factors genes on chromosomes 6,
  16
• Environmental factors Infectious agents
• Cytokines released during Infection Affecting
  APCs (e.g., dendritic cells)
• Cross-reactive amino acid sequences Adenovirus,
  H. pylori

Coeliacs

• Increased frequency of HLA haplotypes
• DR3-DQ2
• DR5/7-DQ2
• DR4-DQ8

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Many and varied Presentations

• Classic Coeliac disease of childhood
• Late Onset GI symptoms
• Altered bowel habit
• Bloating,
• Dyspepsia
• Abdominal discomfort
• Anaemia (iron, folate, B12), coagulopathy
• Asymptomatic coeliac disease (often in relatives)
• Latent Coeliac Disease

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The clinical spectrum of coeliac disease
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Extra-intestinal Manifestations

• Haematological features
• Fe deficiency Anaemia
• Folate deficiency
• B12 deficiency
• Skin diseases
• Dermatitus herpetiformus
• Gynaecological and Obstetric conditions
• Miscarriages
• IUGR
• Infertility

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Extra-intestinal Manifestations

• Musculoskeletal features
• Osteopenic bone disease
• Osteomalacia
• Short stature
• Enamel defects
• Neuropsychiatric disorders
• Peripheral neuropathy
• Ataxia
• Migraines
• Cerebral calcifications
• Fatigue
• Irritability, Depression

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Associated Conditions

• Autoimmune endocrine disorders
• DM type I
• Autoimmune thyroid disease
• Addisons disease
• Autoimmune connective tissue disorders
• Rheumatoid arthritis
• Alopecia areata
• Sjogrens syndrome
• SLE

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Associated Conditions

• Hepatobiliary conditions
• Elevated transaminases
• Primary sclerosing cholangitis
• Autoimmune cholangitis
• Primary biliary cirrhosis
• Other
• Lymphocytic gastritis
• Microscopic colitis
• Downs syndrome, Turners syndrome
• IgA deficiency, IgA nephropathy

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Diagnosis

• Characteristic histological findings
• Clinical, serological, and in some cases,
  histological response to a gluten free diet
• Rarely, observe clinical and histological
  response to gluten challenge
• Some controversy as to whether biopsy is needed
  in all cases but remains the standard of care

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Coeliac Disease Diagnostic criteria

• Major Criteria
• Consistent small bowel Bx
• Positive IgA hTTG serology
• Other Criteria
• Clinical response to GFD
• After serology bx
• Subjective
• Less reliable than IgA TTG serology histology
• Histologic response to GFD
• Relapse with gluten challenge

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Dietary Response to a Gluten Free Diet Is this
Diagnostic?

• Placebo response in IBS up to 70
• Gluten (increased prolamines) is hard to digest
• Gluten free diet often eliminates other dietary
  factors
• Symptomatic response to gluten free diet,
  especially a transient response, does not imply
  the diagnosis is coeliac disease

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Serologic Tests in Adults
Test Sensitivity Specificity
AGA IgA lt 80 in 50 gt 80 in most
AGA IgG Variable Non-specific
EMA IgA 96-97 MO, 90 HUV 100 MO, HUV
tTG IgA 90 GP, 98HR 95 GP, 98 HR
tTG IgG 40 98
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Development of New Serological Tests

• tTG (TG2) has a third function involved in actin
  rearrangement
• Smooth muscle anti-actin antibodies may provide
  another useful serological test in diagnosing
  coeliac disease
• Serum from coeliac with active disease
  preferentially recognise deamidated gliadin
  peptides
• IgA and IgG antibodies to deamidated gliadin
  peptides (DGP) show promise as more sensitive and
  specific tests than IgA and IgG AGA

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What are the Best Serological Tests for Screening?

• Depends on prevalence in and age of population
  being examined
• Overall, tTG IgA is the recommended test to
  screen for disease but sensitivity varies with
  lower levels reported in routine practice
• EMA IgA is helpful when positive
• tTG, EMA less sensitive for milder histologic
  stages
• AGA no longer used as a first line antibody test
  but AGDP has high sensitivity, specificity

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Complicated coeliac sprue

• Complicated sprue Pain/diarrhoea in spite of
  gluten free diet, long period without diet,
  history of small intestinal carcinoma or
  lymphoma, anaemia, pos FOBT
• 87 endoscopic signs of coeliac sprue
• 45 unexpected findings
• 21 Ulcerations
• 1 Small bowel carcinoma
• 1 Submucosal tumour
• 1 Ulcerated nodular Mucosa
• 1 Polyp
• 1 Stricture
• 1 Intussusception

Culliford et al. (2005) GIE 6255 (n 47)
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Coeliac disease Diagnosis

• Villous atrophy (duodenum) total/
  subtotal/partial increased number of
  intraepithelial lymphocytes (IEL)
• Antibodies
• Anti-endomysial IgA
• Anti-transglutaminase IgA
• sensitivity/specificity gt 95
• Response (clinical /histological) to a
  gluten-free diet

HLA DQ2/8 difficult case Consensus NIH
2004Consensus 2004
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Spectrum of Histopathology
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Are Biopsies the Gold Standard?

• False Positives
• Other conditions that cause epithelial changes
  and/ore increased inflammation (peptic
  duodenitis, bacterial overgrowth, enteric
  infection, tropical sprue)
• False Negatives
• Subtle findings, insufficient sample, patchy
  disease, distal disease

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Other causes of Villous Atrophy

• Tropical sprue
• Zollinger-Ellison syndrome
• Common variable immunodeficiency
• Autoimmune enteropathy
• Other immunodeficiency states (usually apparent
  clinically)

• Bacterial overgrowth
• Crohn's disease
• Cow's milk protein intolerance (children)
• Eosinophilic gastroenteritis
• Giardiasis
• Lymphoma
• Peptic duodenitis
• Post gastroenteritis

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HLA DQ Screening Tests

• Increased frequency of certain HLA haplotypes in
  coeliac disease
• DR3-DQ2 or DR5/7-DQ2 95
• DR4-DQ8 5
• Only HLA DQ2 or DQ8 positive subjects are at risk
  of getting coeliac disease screening PCR tests
  are available

• Risk of coeliac disease and HLA status
• General populations 1.0
• DQ2 homozygous-31X
• DQ2/DQ8 positive-14X
• DQ8 homozygous-10X
• DQ2 heterozygous-10X
• DQ8 heterozygous-2X
• DQ2 and DQ8 negative- 0.1X

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Diagnosis of Coeliac Disease
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Risks of coeliac disease and Delayed Diagnosis

• Manifestation of malabsorption
• Anaemia, osteopenia
• Decreased QOL
• Infertility, miscarriages, IUGR
• Malignancy
• Refractory coeliac disease
• Small increase in mortality

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Malignant Complications

• Enteropathy Associated T cell lymphoma (EATCL)
• Other lymphomas
• Small bowel adenocarcinoma
• Oropharyngeal cancer
• Oesophageal squamous cell cancer
• Other malignancies

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Malignant Complications

• Important to note that malignancies with the most
  increased risk in coeliac disease are rare
  cancers in the general population
• NHL 0.5-1 per 1,000,000/yr in western pop
• SB adenoCa 0.6-0.7 per 100,000/yr
• Few studies show increased risk of CRC
• Breast cancer risk is reduced in some studies

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Prognosis

• Generally good prognosis
• Small increase in death rate returns to baseline
  in first few years after diagnosis
• Increased mortality in malabsorptive
  presentations, if diagnosis is delayed, and in
  those poorly compliant with diet
• Main cause of excess death is lymphoma

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Mortality in coeliac Disease
Mortality 95 CI
5 yr survival rate same -
SMR 2.0 1.5-2.7
SMR 2.0 1.8-2.1
SMR 70.9 IBD 36.6-123.9
HR 1.31 1.13-1.51
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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
• Histologic improvement in up to 2 or more years
• Gaining weight above ideal BMI
• Constipation
• Falling off the diet and getting ill again

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Failure to respond to dietary therapy

• Dietary Indiscretion
• Unintentional OR Intentional
• Co-existent conditions
• Lactose intolerance
• Small bowel bacterial overgrowth
• Pancreatic insufficiency
• Microscopic colitis
• IBD
• IBS
• Original diagnosis insecure
• Refractory Coeliac disease

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Refractory Coeliac Disease

• Type I
• Collagenous sprue
• Stricturing and ulcerative coeliac sprue
• Type II
• Clonal T cell expansion (CD3, CD8-)
• Treatment
• Corticosteroids (including budesonide)
• Azathioprine
• Infliximab
• Elemental or parenteral nutrition
• Screen for Enteropathy associated T cell lymphoma

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Why a Gluten Free Diet?

• Probably benefits overall cancer risk
• Improves unexplained infertility
• Ameliorates osteoporosis
• Corrects iron deficiency
• Improved QOL even for those detected by screening
• However, others report decreased QOL adhering to
  a GFD
• GFD is beneficial for preventing, reversing
  and/or treating some complications

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Future Management Strategies

• Alter introduction of gluten during infancy,
  reduce amount of gluten in infant diets
• Breast feeding
• Modify gluten molecules (endopeptidases)
• Genetically modified or less toxic wheat strains
• Inhibit zonulin which regulates intestinal TJs
• Immunotherapy
• Block tTG
• Block HLA DQ2 (DQ8)
• Block T cells or TCR

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What is the Downside to the Over Diagnosis?

• The gluten free diet (GFD)
• Eating out of the home
• Peer pressure for children, teens
• Less acceptable taste, texture of foods
• Cost, availability, labelling
• New therapies on the horizon but are unlikely to
  substitute for a GFD
• Unclear long term benefit of GFD for latent and
  asymptomatic cases detected by screening
• Issues related to insurance, genetic testing, QOL

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Factors leading to Over Diagnosis

• Many patients are at risk
• Every IBS patient may have coeliac disease
• Increased patient awareness
• The wannabe coeliac
• Over sensitive, non-specific serology
• Over-interpretation of biopsies
• Screening of relatives, other asymptomatic
  populations at risk

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Relatives Who and How to Screen

• Index case has proven coeliac disease
• Relative in 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

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Relatives Who and How to Screen
Relative is an appropriate candidate?
Yes - get genetic testing First degree
relatives risk Unknown HLA 10-15 DQ2 or DQ8
- 20-30
No counsel relative and family
HLA DQ2 or 8 positive, check serology
HLA-DQ2 and 8 negative not at risk for coeliac
tTG IgA positive Perform OGD Bx
tTG IgA negative Repeat every few years
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Factors Leading to Under Diagnosis

• Disease presentation
• Classical form less prevalent now
• Other presentations not always considered as
  manifestations of coeliac disease
• Associations of coeliac disease with autoimmune
  and other disorders not always recognised.
• Awareness and understanding of disease by medical
  practitioners
• Use of less sensitive serological assays
• Diagnosis delayed by 11 years in survey data
• Cases continue to be missed in clinical practice

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Take Home Message

• Coeliac disease is not rare (1 in 100-300)
• It can present in many ways and is associated
  with autoimmune diseases
• Public awareness and medical recognition of
  coeliac disease can vary
• Diagnostic tests perform well but have
  limitations
• Together, these factors contribute to both over
  and under diagnosis of coeliac disease
• Implications of this situation are currently
  unknown!

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What to Do with the Patient on a Gluten Free Diet
without Biopsy?
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Management of Coeliac disease

• Evaluate coeliac associated nutritional
  deficiencies
• FBC IrongtFolategtB12 deficiency
• 25-OH vitamin D /- PTH
• Treat deficiencies with GF supplements until
  replete
• Consider associated disorders (DH, thyroid
  disease)
• Educate regarding CD risk in 1o 2o relatives
• Refer for expert dietary counselling
• Gluten free diet
• Lactose free diet for 6/12?
• Monitor clinical serologic response (at 6 12
  months)
• Consider bone mineral density testing at 12 months

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Is screening for coeliac disease justified in
IBS patients?
IgA TTG positive True positive 11 False positive
1
Ig TTG negative but IgG or IgA AGA
positive True positive 3 False positive 51
Sanders et al. Lancet 2001