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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 Precipitating event Immunologic abnormalities 100% Beta cell mass Decline in insulin Intermittent hyperglycemia Blood glucose Normal 0% Time (years) Overt diabetes Model of Autoimmunity B cell Thymus Antibodies FOXp3 IPEX AIRE APS-I Environment Innate Immunity Pathologic T cell HLA APS-II T cell PAE cell CD4 T cell T cell APC CD8 T cell FOXp3 Regulatory T cell Cytokines Periphery 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 Peripheral antigen presentation to thymus APS-I Autosomal recessive Transcription factor in Tcells IPEX X-linked AIRE FOXp3 Autoimmune Polyendocrine Syndromes (APS) Features of APS Feature Inheritance Generation Affected Gene Gender Association Age at Onset Clinical Features APS-I APS-II Autosomal recessive Polygenic Siblings only Multiple generations AIRE mutation HLA-DR3 and DR-4 Equal gender incidence Female preponderance Infancy Peak onset 20-60 years Mucocutaneous candidiasis Hypoparathyroidism Addison disease Type 1 diabetes Autoimmune thyroid disease Addison 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 Peripheral antigen presentation to thymus APS-I Autosomal recessive Transcription factor in Tcells IPEX X-linked AIRE FOXp3 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 8 gm/l 11-14 gm/l Hemoglobin 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 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 Free T4 What is going on? Case 3 Radiology Normal Patient 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 white 50% 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 Positive Negative 78% 15-30% TRAB 24 Hour RAIU 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?