autoimmunity and diabetes robert e. jones, md, facp, face professor of medicine university of utah...
TRANSCRIPT
Autoimmunity and Diabetes
Robert E. Jones, MD, FACP, FACE
Professor of Medicine
University of Utah School of Medicine
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
Immunity
The Players
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
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
T Cell Interactions
Class II MHC
Dendritic Cell
Dendritic Cell
HLA Involvement in Antigen Presentation
Theories of Autoimmunity
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
Celiac Disease
Stages In The Genesis Of Type 1 Diabetes
Beta cell mass
Time (years)
Immunologic abnormalities
Blood glucose
Decline in insulin 100%
0%
Normal
Precipitating event
Intermittent hyperglycemia
Overt diabetes
Model of Autoimmunity
Thymus
Periphery
PAE cell
T cell
T cell
AIREAPS-I
APCCD4 T cell
Regulatory T cell
FOXp3
FOXp3 IPEX
Pathologic T cell
Environment Innate ImmunityHLA
APS-II
CD8 T cell
B cell
Cytokines
Antibodies
Eisenbarth GS, Gottlieb PA. NEJM 204;350:2068-2079.
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
Autoimmune Polyendocrine Syndromes (APS)
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
HypoparathyroidismAddison disease
Type 1 diabetesAutoimmune thyroid
diseaseAddison disease
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 <0.5% Complex evaluation
Gonadal Failure <0.5% History; sex steroid; LH/FSH
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
Cases of Multiple Autoimmune Diseases and Type 1 Diabetes
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?
Examination Case 1
• BP 88/60 mmHg
• Pulse 106 bpm
• Marked hyperpigmentation and vitiligo
• Thyroid slightly enlarged and firm. No nodules
• DTRs demonstrated pseudomyotonia
Laboratory Case 1
Test Result Normal Range
ACTH 2056 pg/ml 9-45 pg/ml
Cortisol 1.7 ug/dl > 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?
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 < 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?
Case 2 Evaluation
• Tests for celiac disease– Tissue transglutaminase antibodies
– Endomysial antibodies
– Antigliadin antibodies (IgA/IgG)
– Biopsy
– Response to a gluten free diet
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?
Case 3 Laboratory
Test Result Normal
ACTH 7 pg/ml 9-45 pg/ml
Cortisol 2.1 ug/dl > 5.0 ug/dl
FSH 1.2 uIU/ml >30 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 < 30 ng/ml >90 ng/ml
Prolactin 3.0 ng/ml <22.0 ng/ml
What is going on?
Case 3 Radiology
PatientNormal
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?
Family History Case 4
Antibodies in Type 1 Diabetes
• Autoantibodies– GAD65– ICA512 (IA-2)– Insulin autoantibodies
Diabetes Type Islet Autoantibodies Comments
Type 1A Positive 90% non-Hispanic white50% black children
Type 1B Negative Rare in whites
Type 2 Negative If antibody is positive, likely a LADA (T1DM)
Other/MODY Negative
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.
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
Case 5 Laboratory
Test Result Normal
TSH <0.01 uIU/ml 0.4-4.0 uIU/ml
Free T4 >7.0 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%
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 <75 mg/dl.
What is her risk for type 1 diabetes?
Case 6 Laboratory
• A GAD65 antibody is ordered and returns positive (7.8 U/ml; normal <5 U/ml)
• Will she develop diabetes?