Autoimmunity and Diabetes

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Autoimmunity and Diabetes

• Robert E. Jones, MD, FACP, FACE
• Professor of Medicine
• University of Utah School of Medicine

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Objectives

1. Understand current concepts in the pathogenesis
   of autoimmunity
2. Learn the different types of the
   immunoendocrinopathy syndromes
3. Recognize the clinical presentations of the more
   common autoimmune conditions associated with type
   1 diabetes

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Immunity
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The Players
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Innate v Adaptive Immunity

• Innate immunity helps in the defense against a
  new unrecognized assault
• Nonspecific
• Tuberculosis, foreign body, etc
• Adaptive immunity is very specific
• Repeated antigen exposure
• Immunization

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HLA Antigens

• HLA refers to Human Leukocyte Antigens
• MHC refers to major histocompatibility complex
• Class I MHC antigens
• Class II MHC antigens
• Only found on professional antigen presenting
  cells
• HLA DP DQ DR
• Resemble a hot dog and bun
• Hot dog processed antigenic peptide
• Bun groove of histocompatibility molecule

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T Cell Interactions
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Dendritic Cell
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Dendritic Cell
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HLA Involvement in Antigen Presentation
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Theories of Autoimmunity
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Inciting Events and Natural Prevention

• Triggers
• Viral infection
• Antigenic mimicry
• Presentation error
• Tolerance
• Recognition of self
• Very complicated and involves the development of
  thymic T-cells and linked recognition

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Celiac Disease
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Stages In The Genesis Of Type 1 Diabetes
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Blood glucose
Beta cell mass
Normal
0
Time (years)
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Model of Autoimmunity
B cell
Thymus
Antibodies
Environment Innate Immunity
Pathologic T cell
FOXp3 IPEX
AIREAPS-I
HLA APS-II
T cell
PAE cell
APC
CD4 T cell
CD8 T cell
FOXp3
T cell
Regulatory T cell
Cytokines
Periphery
Eisenbarth GS, Gottlieb PA. NEJM
2043502068-2079.
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Genetic Associations
Gene Proposed Mechanism Disease Inheritance
HLA Antigen presentation APS-II Multigenic
MIC-A Priming of T-cells Type 1 diabetes celiac Addison Multigenic
PTPN22 T-cell receptor signaling Type 1 diabetes RA SLE Multigenic
CTLA-4 Reduces T-cell activation Type 1 diabetes thyroid celiac Addison Multigenic
AIRE Peripheral antigen presentation to thymus APS-I Autosomal recessive
FOXp3 Transcription factor in T-cells IPEX X-linked
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Autoimmune Polyendocrine Syndromes (APS)
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Features of APS
Feature APS-I APS-II
Inheritance Autosomal recessive Polygenic
Generation Affected Siblings only Multiple generations
Gene AIRE mutation HLA-DR3 and DR-4
Gender Association Equal gender incidence Female preponderance
Age at Onset Infancy Peak onset 20-60 years
Clinical Features Mucocutaneous candidiasis Hypoparathyroidism Addison disease Type 1 diabetes Autoimmune thyroid disease Addison disease
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Autoimmune Conditions Associated with T1DM
Associated Disease Frequency Recommended Evaluation
Addison Disease 0.5 ACTH 21-hydroxylase antibodies
Hashimoto Thryoiditis 15-30 TSH TPO or Tg antibodies
Celiac Disease 5-10 Transglutaminase antibodies biopsy
Vitiligo 1-9 Examination
Pernicious Anemia 0.5-5 CBC B-12 anti-intrinsic factor antibody
IgA Deficiency 0.5 IgA levels
Hypophysitis lt0.5 Complex evaluation
Gonadal Failure lt0.5 History sex steroid LH/FSH
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Genetic Associations
Gene Proposed Mechanism Disease Inheritance
HLA Antigen presentation APS-II Multigenic
MIC-A Priming of T-cells Type 1 diabetes celiac Addison Multigenic
PTPN22 T-cell receptor signaling Type 1 diabetes RA SLE Multigenic
CTLA-4 Reduces T-cell activation Type 1 diabetes thyroid celiac Addison Multigenic
AIRE Peripheral antigen presentation to thymus APS-I Autosomal recessive
FOXp3 Transcription factor in T-cells IPEX X-linked
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Cases of Multiple Autoimmune Diseases and Type 1
Diabetes
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Case 1

• The patient is a 34 year old man who is referred
  for management of type 1 diabetes. He had
  enjoyed reasonable glycemic control (A1Cs
  7.0-8.2) and had been on an insulin pump for
  several years. Type 1 diabetes was diagnosed 7
  years ago and he had no evidence of clinical
  complications .
• His profession involved travel, and he was
  recently admitted to a hospital because of severe
  hypoglycemia. In retrospect, he had noticed and
  increasing frequency of hypoglycemia over the
  preceding several months. He had also noted
  weight loss, nausea and fatigue.
• What causes increasing hypoglycemia in patients?
  

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Examination Case 1

• BP 88/60 mmHg
• Pulse 106 bpm
• Marked hyperpigmentation and vitiligo
• Thyroid slightly enlarged and firm. No nodules
• DTRs demonstrated pseudomyotonia

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Laboratory Case 1
Test Result Normal Range
ACTH 2056 pg/ml 9-45 pg/ml
Cortisol 1.7 ug/dl gt 5.0 ug/dl
TSH 45 uIU/ml 0.3-4.0 uIU/ml
Free T4 0.5 ng/ml 0.8-1.7 ng/ml
Sodium 129 mEq/l 136-146 mEq/l
Potassium 6.4 mEq/l 3.7-5.1 mEq/l
Hemoglobin 8 gm/l 11-14 gm/l
What is your diagnosis?
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Case 2

• A 43 year old woman is seen in follow up of type
  1 diabetes and hypothyroidism. She has always
  been under excellent control (A1C lt 7.0) and her
  TSH was always normal on levothyroxine. She had
  recently noted a progressive feeling of fatigue.
  She had at least 3 episodes of food poisoning
  due to bad mayonnaise and found it harder to
  recover after each event.
• Routine labs documented abnormal liver functions
  with a low albumin anemia and her TSH was 22
  uIU/L.
• What organ systems are involved? What are your
  thoughts?

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Case 2 Evaluation

• Tests for celiac disease
• Tissue transglutaminase antibodies
• Endomysial antibodies
• Antigliadin antibodies (IgA/IgG)
• Biopsy
• Response to a gluten free diet

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Case 3

• A 57 year old woman comes to clinic for
  evaluation of type 1 diabetes. She feels
  terrible. Fatigue, hypoglycemia, headaches and
  dizziness are her complaints. Her A1C is 5.7 .
• Physical examination reveals a chronically ill
  woman without focal findings.
• Initial laboratory tests document hyponatremia
  (128 mEq/l), hypokalemia (3.1 mEq/l) and anemia.
  TSH is normal (1.2 uIU/l) and free T4 is low (0.6
  ug/ml).
• Any other tests? Any thoughts?

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Case 3 Laboratory
Test Result Normal
ACTH 7 pg/ml 9-45 pg/ml
Cortisol 2.1 ug/dl gt 5.0 ug/dl
FSH 1.2 uIU/ml gt30 uIU/ml (menopausal)
TSH 1.2 uIU/ml 0.3-4.0 uIU/ml
Free T4 0.6 ng/dl 0.8-1.7 ng/ml
IGF-1 lt 30 ng/ml gt90 ng/ml
Prolactin 3.0 ng/ml lt22.0 ng/ml
What is going on?
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Case 3 Radiology
Patient
Normal
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Case 4

• A 57 year old woman is referred for management of
  poorly controlled type 2 diabetes. She has been
  effectively managed with oral agents but her most
  recent A1C was 9.2. She also has rheumatoid
  arthritis, hypothyroidism and vitiligo. She has
  also noted a worsening of depressive symptoms.
• Her BMI is 38 kg/m2.
• What is the issue with this patient?

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Family History Case 4
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Antibodies in Type 1 Diabetes

• Autoantibodies
• GAD65
• ICA512 (IA-2)
• Insulin autoantibodies

Diabetes Type Islet Autoantibodies Comments
Type 1A Positive 90 non-Hispanic white 50 black children
Type 1B Negative Rare in whites
Type 2 Negative If antibody is positive, likely a LADA (T1DM)
Other/MODY Negative
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Case 5

• You are seeing an old patient in follow up. Her
  last visit was two years ago. She has type 1
  diabetes that had been very well controlled, but
  recently, she has noted that her glucose control
  has deteriorated. She reports taking much more
  insulin with less effect. She also notes
  frequent insulin shock with symptoms of
  palpitations, sweating and tremor, but she is
  puzzled because her symptoms can occur with
  glucose values over 200 mg/dl. She has also lost
  15 pounds.

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Case 5 Examination

• BP 136/50 mmHg
• P 120 bpm
• Pronounced stare with exopthalmus
• Thyroid enlarged with distinct bruit
• Fine tremor
• Skin warm and moist

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Case 5 Laboratory
Test Result Normal
TSH lt0.01 uIU/ml 0.4-4.0 uIU/ml
Free T4 gt7.0 ng/ml 0.8-1.7 ng/ml
Total T3 567 pg/ml 70-180 pg/ml
TRAB Positive Negative
24 Hour RAIU 78 15-30
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Case 6

• A 47 year old woman is seen with a very simple
  question, will I develop type 1 diabetes?
• She has hypothyroidism due to chronic lymphocytic
  thyroiditis and is on levothyroxine. Her family
  history is filled with autoimmune thyroid disease
  and type 1 diabetes. She is unaware of any
  endocrinopathy in her family.
• She has been dying her hair for 20 years because
  of silvering which is aa common family trait.
• Her A1C is 5.3 and her fasting glucose values
  are always lt75 mg/dl.
• What is her risk for type 1 diabetes?

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Case 6 Laboratory

• A GAD65 antibody is ordered and returns positive
  (7.8 U/ml normal lt5 U/ml)
• Will she develop diabetes?

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