Should all children with type 1 diabetes be screened for celiac disease?

Edwin Liu, MDedwin.Liu@childrenscolorado.org

Screening-identified patient

• 15 yo with type 1 diabetes (T1DM) diagnosed at age 6.

• Recently screened for CD tTG+• His mother wants to pursue biopsy, wants

to prevent future potential complications.• Patient unsure, but will do whatever his

doctors recommend.• Asymptomatic, good growth, normal

nutritional labs, normal DEXA.

Biopsy showed Marsh 3 lesions, diagnosed with CD

• Started the gluten-free diet (GFD).• tTG autoantibodies resolve.• Follow-up over the next 2 years, remains

adherent to the diet but feels no different.• He wants to be a good patient, but admits

that the diet is difficult.

So, what is the rationale for screening and treating CD in this patient? Are we doing him

any favors?

Screening Recommendations

AGA ADA

NASPGHAN ESPGHAN

Screening Recommendations

AGA

It is the position of the American Gastroenterological Association (AGA) Institute that testing for celiac disease (CD) should be considered in symptomatic individuals who are at particularly high risk.

Screening Recommendations

ADAPatients with type 1 diabetes (T1DM) should be screened for celiac disease.

Positive antibody levels should be confirmed.

Referral to a gastroenterologist for consultation.

Screening Recommendations

NASPGHAN

It is also recommended to test asymptomatic children who belong to specific groups at risk…type 1 diabetes

Screening Recommendations

ESPGHAN

Testing for CD should be offered to asymptomatic children and adolescents with an increased risk for CD such as T1DM

Screening T1DM for CD

• Primary reason for screening is because having T1DM is a risk factor for developing CD– The same reasons for screening any other

group at risk for CD should apply to screening in T1DM

– But are there any specific benefits (or potential harm) to screening and treating for CD in T1DM?

Considerations for generalized screening of CD in T1DM

• What is the risk of developing CD with T1DM?• Will all individuals with asymptomatic CD

develop long-term complications?– If not, should we treat every patient with

asymptomatic CD to prevent complications in just a subset of patients?

• What are the potential benefits and potential harmful effects of gluten-free diet in T1DM?

More questions than answers!

CD and T1DM share DR3-DQ2 and DR4-DQ8 as part of their risk

The major haplotype, DR3-DQ2 is present in:• 90% of patients with CD• 55% of patients with T1DM• 20-25% of general population of European

ancestry

What is the frequency of Celiac Disease in T1DM?

T1DM 4-12%

T1DM (DQ2/DQ2) 33%Bao, J Autoimmunity 1999

The co-occurrence of both CD and T1DM are mainly dependent on shared HLA

An example of how we can learn from the study of other autoimmune diseases:

Natural History Studies in Type 1 Diabetes

Observational, prospective, birth cohort studies to look at the natural history of islet autoimmunity, and to identify environmental triggers

• Germany – BABYDIAB

• Finland – DIPP (Type 1 Diabetes Prediction and Prevention Project)

• Denver – DAISY (Diabetes Autoimmune Study of the Young)

• Multinational – TEDDY (The Environmental Determinants of Diabetes in the Young)

Given the shared HLA risks, subjects are also monitored for CD in these studies!

DR3-DQ2/DR4-DQ8

DR4-DQ8/DR4-DQ8

DQ8

DQ2

BABYDIAB studyDR3-DQ2/DR4-DQ8 is the highest risk for

T1DM, followed by DR4-DQ8/DR4-DQ8

Achenbach P et al. Diabetes 2005;54:S25-S31

DQ8/DQ8

DQ2/DQ8

% T

ype

1 D

iabe

tes

auto

antib

odie

s

HLA group % incidenceat 10 years

DQ2/DQ2 17.9%DQ2/DQ8 13.7%

DQ2/X 13.8%DQ8/DQ8 7.3%

DQ8/X 3.2%

Cel

iac

Aut

oim

mun

ity (%

)

Age (years)

DQ2/DQ2DQ2/DQ8

DQ2/X

DQ8/XDQ8/DQ8

DAISY StudyDR3-DQ2/DR3-DQ2 is the highest risk

for CD, followed by DR3-DQ2

Natural history of untreated CD?• Burden of untreated symptomatic CD is well

described• What about untreated subclinical CD in adults?

– 4x increased mortality in young adults– Limited morbidity and no increase in mortality in older

individuals• Lower ferritin levels• Reduced bone density• Lower BMI and cholesterol (favorable)

• Undiagnosed CD can confer benefits and liabilities to older individuals.

Godfrey JD, Gastro 2011

Rubio-Tapia A, Gastro 2009More studies needed to determine the

natural history of screening-identified CD

Does GFD prevent autoimmunity?• Rationale

– Anti-tTG develop in NOD mice• Sblattero D, J Immunol 2005

– Prevention of T1DM in NOD mice with various dietary interventions

– Early dietary factors (cereal exposure) affects risk of T1DM in humans

• Zeigler A, JAMA 2003• Norris J, JAMA 2003

No good clinical studies to indicate that GFD will prevent T1DM

Will untreated celiac disease lead to development of other autoimmunity?

1. Ventura A, Gastroenterology 1999

2. Ventura A, J Pediatr 2000

3. Cosne J, Clin Gastroenter Hepatol 2008

1. Sategna Guidetti C, Gut 2001

2. Ansaldi N, J Pediatr Gastroenterol Nutr 2003

3. Viljamaa M, Scand J Gastroenterol 2005

4. Meloni A, J Pediatr 2009

No Yes

Data is mixed about autoimmune thyroiditis and other autoimmunity in association with duration

of gluten exposure

Determine the benefits of screening for tTG+ in children with T1DM

Baseline characteristics• 79 children with T1DM and tTG+, and 56 T1DM and tTG-

children followed for 2 years• Body composition, bone health and nutritional markers

evaluated at baseline, 1 year and 2 years.

BASELINE:• tTG+ children had altered body composition but not

reduced bone mineral density (BMD) compared to tTG-.• tTG+ children self-selected for GFD (43) or regular diet

(36)• No difference in symptoms

2-year findings• tTG+ children maintained (at baseline and at 2 years)

consistently lower scores for weight and BMI and increased bone turnover than tTG- subjects.

• No difference in HbA1c levels and frequency of hypoglycemic episodes

• No significant differences in tTG+ patients following a GFD vs regular diet, including symptoms.

• Half of children reportedly following GFD have remained persistently tTG+

• Children with persistent high tTG levels (>10x) had also reduced BMD, vitamin D, and ferritin levels

Limitations of the ROSE study

• Not randomized• Some crossover between GFD and regular diet

– reflects the changing attitudes of parents regarding GFD in tTG+ children

• Two-year follow-up may be too short to find differences in bone density/growth

• Smaller numbers were not powered to determine an absence of a difference between tTG+ and tTG- groups.

Summary• No differences in metabolic control in tTG+

children vs tTG- children

• Limited adverse outcomes in tTG+ children who remained untreated over 2 years compared to tTG- children

• Persistence of tTG at high levels should be a reason for concern, regardless of reported dietary compliance.

• There may not be a rush to treat for CD in patients with T1DM

What is the evidence that celiac disease affects individuals with type 1 diabetes?

# CD and T1DM

Condition at presentation Findings

*Simmons 2011 79Screening-identified children

Higher persistent tTG levels had lower bone mineral density z-scores, ferritin, and vitamin D levels after 2 years

Freemark 2008 30 Asymptomatic children

High tTG levels correlated with lower weight and BMD

Leeds 2011 12Newly

diagnosed adults

Worse glycemic control, higher prevalence of retinopathy and nephropathy at diagnosis

Pitocco 2011 30 Adults, existing CD

T1DM+CD show more severe subclinical atherosclerosis compared to those presenting T1DM or CD only

All studies compared type 1 diabetics with CD vs without CD*indicates prospective evaluation

What is the effect of GFD in T1DM?# children Duration of

follow-up Benefit of GFD

*Husby 2006 33 2 years Improved SDS height & weight, hemoglobin, ferritin

*Dunger 2002 11 2 years Improved BMI and HbA1C

Stern 2005 9 1-6 years Improved SDS height, HbA1C, anemia

Catto-Smith 2004 21 1 year Improved growth, glucose control

Abid 2011 23 1 year Improves symptoms and hypogycemia, increased insulin requirements.

Protheroe 2009 22 1 year Resolution of symptoms and improved nutritional status with GFD

Rami 2005 98 > 1 year Decreased weight gain, but no effect on metabolic control

Goh 2010 29 1 year Asymptomatic children, no significant changes in BMI, height Z-score or metabolic control

Chan 1999 20 ? No benefit, no difference from type 1 diabetic controls

All studies compared type 1 diabetics with CD vs without CD*indicates prospective evaluation

My conclusions from these studies of CD and T1DM

• Some differences in outcomes may be related to phenotype of CD – some groups more symptomatic than others

• In asymptomatic cases, the benefit of GFD appears to be mainly limited to growth and bone health

• Trend towards improved metabolic control (HgbA1c, hypoglycemic episodes) and increased insulin requirements

• 2 years prospective follow-up likely not sufficient to detect potential long-term complications

How does Celiac Disease affect Quality of Life in T1DM?

• The “double” diagnosis of CD has minimal impact on quality of life in children with T1DM– however, parents of CD + T1DM children did express greater

concern about their child's social functioning.

• Most celiac patients found it challenging to adhere to a GFD– Challenging diet was associated with reductions in patient

wellbeing and increased psychological distress

Sud S, Pediatr Diabetes 2012Barratt J Gastrointestin Liver Dis 2011

Screening for CD in T1DM

If symptomatic CD, then there is a clear benefit from GFD

Many screening-identified children do not have symptoms

Possible increase in mortality Prevention of morbidity and mortality is not known

Most patients with apparently silent CD were not completely asymptomatic

In asymptomatic cases the benefit appears to be limited to growth and bone mineralization

Increased risk of hypoglycemia, higher HbA1c, impaired growth, bone mineralization and possibly atherosclerosis

May have a significant impact on quality of life

Treatment is readily available Poor adherence to GFD (only about 50%).

FOR AGAINST

What evidence is lacking?• *No evidence that celiac autoimmunity predisposes to anti-islet

autoimmunity

• *No evidence that GFD reduces risk of anti-islet autoimmunity

• No compelling long-term prospective evidence to date to show

that asymptomatic children have significant long-term

consequences

• No strong long-term prospective controlled studies to support

GFD in type 1 diabetes (data on metabolic control is growing,

but not unanimously positive)

*negative studies

Recommendations for CD in T1DM• Should they be screened?

– High incidence – yes– annually, or if symptoms develop

• Should they be treated?– Reasons FOR and AGAINST treatment.– If symptomatic – no debate– If asymptomatic – look for pre-existing complications. If present,

then treat.– Otherwise, recommend thoughtful discussions with

patients/families. There may not be a rush to diagnose and treat!

– Bias towards being more conservative and recommend treatment in children – (they need to grow and develop, current data is not definitive)

Larger controlled, randomized prospective studies needed to determine natural history.

One final thought: Should children with CD be screened for T1DM?

• No recommendations at present for screening with islet autoantibodies in a patient with CD

• Low risk to develop diabetes:– HR 2.4 (95%CI 1.9-3.0) vs matched controls

followed to age 20 years

D’Annunzio G, Diabetes Care 2009

Ludvigsson Diabetes Care 2006

HLA genotypes in T1DM are more permissive for the development of CD, but not vice versa

HLA genotype frequencies for Denver general population

Vast majority of CD will have one of these

genotypes

HLADistribution

(%)DQ2/DQ2 1.1DQ2/DQ8 2.3

DQ2/X 17.1DQ8/DQ8 2.2

DQ8/X 17.3X/X 60.0

Highest risk genotypes for

T1DM

Could we adopt a personalized screening strategy for T1DM in celiac patients?

The Environmental Determinants of Diabetes in the Young

Age at developing tTG autoantibodies (Months)

Kap

lan-

Mei

er e

stim

ates

0 12 24 36 48 60 72 84

0.5

0.6

0.7

0.8

0.9

1.0

tTG autoantibodies

DR3-DQ2/DR3-DQ2 DR3-DQ2/DR4-DQ8DR4-DQ8/DR4-DQ8DR4-DQ8/DR8

Log-rank test p-value<0.0001

DR4-DQ8/DR8DR4-DQ8/DR4-DQ8DR3-DQ2/DR4-DQ8DR3-DQ2/DR3-DQ2Number of subjects at risk

901999

2052988

647702

1347595

362413789345

205237381151

DQ2/DQ2

DQ8

DQ8/DQ8

DQ2/DQ8

% w

ithou

t tTG

aut

oant

ibod

ies

Age at developing tTG autoantibodies (months)

Time to persistent tTG by HLA

TEDDY StudyDQ2/DQ2 is the highest risk for CD,

followed by DQ2/X