Type 1 Diabetes Mellitus

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Type 1 Diabetes Mellitus Coeliac Disease
Dr. Majeed Mustafa , FRCP Consultant
Endocrinologist Diabetologist GDC Hospital ,
Abu Dhabi 25th April 2009
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Type 1 Diabetes

• 5 of total diabetes population
• Mostly children , adolescents and young adults
• Auto immunity Present in 90 of patients
• Insulin Ab , ICA , GAD 65
• Unknown 10 of patients.

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Incidence of Type 1 Diabetes
Number of cases per 100000/year
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Auto Immune Destruction of B Cells
Normal Islets of Langerhan
Insulitis
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Natural History of Type 1 Diabetes
Genetic predisposition
Antibodies produced against ß cells GAD 65
Loss of 1st phase insulin secretion
Environmental factors
Cell mass ß
Destruction of ß cells
Prediabetes
Diabetes
Time
Clinical presentation
J. Skyler
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• Causes of Type 1 DiabetesEnvironment Factors

Causes of Type 1 Diabetes Genetic Factors
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Coeliac Disease

• Celiac disease is an immune-mediated
• enteropathy affecting mainly the proximal
• small intestine caused by a permanent
• sensitivity to gluten in genetically
• susceptible individual
• Commonest autoimmune disorder worldwide

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The oldCoeliac Disease Epidemiology

• A rare disorder typical of infants and young
• children
• Wide range incidence
• 1/400 Ireland
• 1/10000 Denmark
• A disease of European
• origin

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The Changing Coeliac Epidemiology

• The availability of sensitive serological markers
  made it
• possible to discover Coeliac Disease even when
  the
• clinical suspicion was low
• AGA Anti EMA
  Anti TTG
• 1980 1990
  2000

Classical Children , MAS
Current Concept Children Adults Asymptomatic
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Effect of Serological Screening on CD Prevalence
Country Prevalence
on Prevalence on
clinical diagnosis
screening data
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Spectrum of Clinical Manifestations of Coeliac
Disease
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Coeliac Disease Genetic Predisposition

• Susceptibility to celiac disease is determined to
  a significant extent by genetic factors
• Positive family history
• First-degree relatives concordance 1015 1
• Monozygotic twins concordance 80 2
• 1.MacDonald WC, et al ,1965 N Engl J Med
  272448456
• 2.Hervonen K et al , J Invest Dermatol. 2000
  Dec115(6)990-3.

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Coeliac Disease Genetic Predisposition

• This susceptibility has been localized to
• the HLA region of chromosome 6.
• 90 of CD patients share the HLA DR3-HLA DQ2 .
  1
• 10 express the DR4-DQ8 haplotype. 2
• 1.Sollid LM, et al 1989 J Exp Med 169345350
• 2. Michalski JP, et al. Tissue Antigens 4712713

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Disease Association of Coeliac Disease

• Type 1 Diabetes Mellitus (2-8)
• Thyroid disease (5)
• Primary biliary cirrhosis (3)
• Sjögren's syndrome (3)
• IgA deficiency (2)
• Pernicious anaemia

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Disease Association of Coeliac Disease

• Inflammatory bowel disease
• Sarcoidosis
• Myasthenia gravis
• Neurological complications cerebellar atrophy,
  peripheral neuropathy, epilepsy
• Dermatitis herpetiformis

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Disease Association of Coeliac Disease

• Down's syndrome
• Enteropathy-associated T-cell lymphoma
• Small bowel carcinoma
• Squamous carcinoma of oesophagus
• Ulcerative jejunitis
• Pancreatic insufficiency
• Splenic atrophy

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Genetic Predisposition Type 1 Diabetes CD

• Sharing of a common genetic factor in the HLA
  region 1,2
• Diabetic susceptibility, is associated with HLA
  DR3-DQ2 and DR4-DQ8 similar to CD .
• 1.Buzetti R, Quattrocchi CC, Nistico L 1998 .
  Diabetes Metab Rev 14111128
• 2.Atkinson MA, Eisenbarth GS 2001 Lancet
  358221229

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Genetic Predisposition

• The prevalence of HLA DQ2 is 2030 in the
• general population , and only a minority of
  these
• will ever develop CD. 1
• The involvement of additional, probably non- HLA
  linked genes in the pathogenesis of CD
• 1.Polvi A, et al ,1996. Eur J Immunogen 23221234

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HLA in CD and DM

• HLA typing should not be used in the
• diagnosis of CD in patients with type 1 DM
• because of the similarities of HLA types in
• patients with type 1 DM and those with CD.
• Doolan A, Diabetes Care 28806-809, 2005

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CD and Type 2 Diabetes

• In contrast to type 1 diabetes, there is no
  evidence that the risk of coeliac disease
  in type 2 DM is increased compared with the
  general population.
• Sjöberg K, et al 1998 . J Intern Med 243133140
• Page SR, et al 1994 . Q J Med 87631637

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Which Came First ??
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Which Came First ??

• Type 1 diabetes almost always precedes
• the diagnosis of CD which is usually
• diagnosed during the first year following
• DM diagnosis by serological screening
• Saukkonen T, et al 1996 . Diabet Med
  13464470

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Which Came First ??

• Type 1 diabetes patients who are initially
• CD antibody negative could undergone
• seroconversion and contracted coeliac
• disease during follow-up
• Mäki M, et al 1984. J Pediatr 105901905
  .Catassi C, et al 1991 . Eur J Pediatr
  150832834
• Cacciari E 1997, et al. Arch Dis Child 77465
  .Lorini R, et al 1996 . J Diabetes Complications
• 10154159

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Coeliac Disease Triples Risk of Type 1 Diabetes  

• Swedish National inpatient register (
  1964-2003) identify 9243 individuals with CD
  diagnosed before age 20 years.
• These patients were matched to five reference
  subjects without CD by age, gender, calendar
  year, and area of residence (n 45,680).
• The median age at CD diagnosis was 1 year, while
  the median age of type 1 diabetes diagnosis was
  10 years among patients with a prior CD
  diagnosis.
• Jonas F. Ludvigsson ,Diabetes Care.
  2006292483-2488.

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Coeliac Disease Triples Risk of Type 1 Diabetes  

• Children with CD had increased hazard ratio of
• 2.4 for a subsequent diagnosis of type 1
  diabetes
• before age 20.
• No evidence that an earlier introduction of a
• gluten-free diet in patients with CD protects
  against type 1 diabetes
• Jonas F. Ludvigsson ,Diabetes Care.
  2006292483-2488

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Clinical Manifestations of Coeliac Disease

• Since the development of serological screening
  tests for CD, it has become evident that the
  common symptoms constitute only a minor component
  in the concept of CD , In the majority of cases
• Clinically silent
• Extra gastrointestinal symptoms

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Clinical Manifestations of Coeliac Disease

• Since 1960 ,a shift toward milder symptoms has
  occurred, both in children and adults
• Steatorrhea and profuse diarrhea are relatively
  rare
• Patients often suffer only from occasional loose
  stools
• Malabsorption may be subclinical
• Severe forms are infrequent

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Clinical Manifestations of Coeliac Disease

• Nutrients malabsorption
• Anemia iron or folic acid deficiency
• less commonly of cobalamin.
• Hypocalcemia
• Hypoproteinemia
• Fat-soluble vitamins D , less often K .
• Constipation, overweight, or obesity do not
  exclude coeliac disease

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Extraintestinal and Atypical Manifestations
Dermatitis Herpetiformis

• Erythematous macule gt urticarial papule gt tense
• vesicles ,Symmetric distribution
• Severe pruritus
• No GI symptoms 90
• Villous atrophy 75
• Gluten sensitive
• Garioch JJ, et al. Br J Dermatol. 1994131822-6.
  Fry L. Baillieres Clin Gastroenterol.
• 19959371-93. Reunala T, et al. Br J Dermatol.
  1997136-315-8.

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Extraintestinal and Atypical Manifestations

• Recurrent oral aphthous ulcerations

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Extraintestinal and Atypical Manifestations

• Enamel defects in the
• permanent teeth may
• be the only
• manifestations of CD

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Extraintestinal and Atypical Manifestations

• Osteoporosis Osteomalacia
• Low BMD
• Improve on
• GFD

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Extraintestinal and Atypical Manifestations

• Neurological symptoms
• Peripheral neuropathy
• Memory loss
• Ataxia
• Epilepsy Cranial
• calcification
• Severe proximal myopathy

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Extra intestinal and Atypical Manifestations

• Sjögrens syndrome
• Nonspecific arthritis
• Juvenile arthritis
• Arthralgia
• Immune hepatitis

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Clinical Features of CD in Type 1 Diabetes

• Mostly asymptomatic 60 of children
• Silent Positive serology , Abnormal jejunal
  biopsy
• Identified by screening
• Latent No symptoms Normal mucosa Positive
  serology
• Develop mucosal damage Symptoms on follow up

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Clinical Features of CD in Type 1 Diabetes

• Recurrent unexplained hypoglycemia
• followed by ketosis
• Decrease Insulin requirement
• ?? Honeymoon Period
• Poor Glycemic Control
• (Brittled Diabetics)

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Depletion of CHO Stores
Recurrent Hypos followed by DKA
Recurrent Hypoglycemia
CHO Malabsorption
Sympathetic Stimulation
Normoglycemic Ketosis (Starvation Ketosis)
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Coeliac Disease Associated with Increased TB Risk

• The occurrence of TB in 14,335 patients with CD
  and in 69,888 matched normal subjects
• The presence of CD raised the risk of TB by 3.74
  fold
• Subjects with prior TB were 2.5-times more likely
  to have CD
• Jonas F. Ludvigsson ,Thorax 2006

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Malignancy in Coeliac Disease

• T-cell Lymphoma Rare
• Suspect if long history of celiac disease and
• Reversal of response to gluten withdrawal
  with
• Fever
• Weight loss
• Abdominal pain

• Finger clubbing
• Bowel ulcerations
• Sustained rise in serum
• IgA levels

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Malignancy in Coeliac Disease

• T- and B-cell non-Hodgkin lymphoma.
• Adenocarcinoma of the
• Oropharynx, Esophagus, Pancreas
• Small and large bowel
• Hepatobiliary tract

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Starvation Ketosis

• Very mild symptoms nausea , fatigue
• Good hydration
• Normal B. glucose or Mild moderate
  hyperglycemia
• Normal electrolytes
• Absent or mild acidosis.
• Simply corrected by IV glucose insulin

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Clinical Features of CD in Type 1 Diabetes

• Iron or folic acid deficiency
• Infertility
• Short stature 30 of children with CD
• 10 of children and teens with short stature
• have CD
• Severe malabsorption is unusual

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Clinical Features of CD in Type 1 Diabetes

• Delayed menarche in untreated female teens
• Bleeding tendency
• Unexplained urticaria
• Unexplained elevated liver enzymes (ALT,AST)
• 9 of adults have silent CD
• Usually normalized on GFD

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Problems of CD Diagnosis in Type 1 Diabetes

• Silent
• Weight loss
• Hypoglycemia
• Chronic diarrhea
• Growth retardation
• Peripheral neuropathy

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Serological Test Comparison

• Sensitivity
  Specificity
• AGA-IgG 69 85
  73 90
• AGA-IgA 75 90
  82 95
• EMA (IgA) 85 98
  97 100
• TTG (IgA) 90 98
  94 97
• Farrell RJ, and Kelly CP. Am J Gastroenterol
  2001963237-46.

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Diagnosis of Coeliac Disease

• Typical histopathology
• Total or subtotal villous
• atrophy
• Chronic inflammary cell
• infilteration
• Intraepithelial lymphocytes

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Screening For CD in Type 1 Diabetics

• Screening for CD is indicated in
• Newly diagnosed type 1 diabetics
• Those who developed diabetes within the previous
  4 years.
• At any time if child or adolescent develops
  intestinal or extra-intestinal symptoms
  consistent with CD.

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GFD Diabetes

• Exclusion of wheat, rye, barley and initially
  oats which may be reintroduced safely in most
  patients.
• Rice, maize and potatoes are satisfactory
  sources of alternative complex carbohydrates.

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Diabetes and GFD Management Guidelines

• CHO 55 60 of total calories intake
• GFD More burden on an already restricted
  diet
• Insulin requirement usually increase following
  GFD
• Patients should check BG levels before meals and
• snacks to determine their insulin dose as often
  as
• possible
• Postprandial BGs to determine
• how different GF grains or CHO affect the BG

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Diabetes and GFD Management Guidelines

• Promote CHO consistency
• Daily 210240 grams will be adequate for most
  individuals.
• CHO should be spread evenly across meals and
  snacks throughout the day to maintain more stable
  BG levels.
• If six small meals were eaten throughout the
  day, each should consist of approximately
  3045grams

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Diabetes and GFD Management Guidelines

• Promote GF whole grains, fruit, vegetables,
• legumes and low-fat dairy products
• A basal-bolus regimen may be helpful to promote
  optimal glucose control. Basal insulin is
  combined with rapid-acting insulin before
  meals.
• Insulin therapy should be individualized based on
  the patients ability to do the required
  calculations and willingness to take multiple
  daily injections.

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Going Natural

• Commercial GF products expensive
• Make GF substitutions using naturally GF foods
• Rice bread
• Asian rice pasta in place of regular pasta
• Corn tortillas instead of flour tortillas

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