Autoimmune polyendocrine syndromes

1. Autoimmune
polyglandular syndromes.
Types, pathogenesis, diagnosis, management
Dr. Tarun P Betha
2nd year internal medicine resident
Poona hospital and research centre
1

2. Outline
• Introduction
• Types
• APS1
• APS2
• IPEX
2

3. Introduction
Autoimmune polyendocrine syndromes are
insidious and are characterised by circulating
autoantibodies and lymphocytic infiltration of
the endocrine tissues and organs, eventually
leading to organ failure.
3
Source: Cecil textbook of medicine

4. Types
• Autoimmune polyglandular syndrome type 1
• Autoimmune polyglandular syndrome type 2
• IPEX*
4
*immunedysregulation, polyendocrinopathy, enteropathy, x linked

5. Autoimmune polyglandular
syndrome type 1
• Also called polyendocrinopathy-candidiasis-
Ectodermal dystrophy. (APECED)
• Autosomal recessive.
• Mutation in AIRE gene.
• Highest prevalence in Finnish countries.
5

6. APS1 cont’d
Cardinal components
Hypoparathyroidism
Addisson’s disease
Chronic mucocutaneous candidasis
6

7. • Enamel hypoplasia
• Premature ovarian failure (60% in females)
• Testicular failure (rare)
• Bilateral keratitis
• Autoimmune hepatitis
• Nephritis, pancreatitis, asplenia.
7
APS1 cont’d
Other features

8. • Chronic mucocutaneous candidiasis- squamous
cell Ca (common cause of death)
• Other causes of death include- Hypocalcemic
crisis, adrenal crisis.
8
APS1 cont’d

9. 9
APS1 cont’d
Genetics and mechanisms
‘AIRE’ gene
mTEC medullary thymic epithelial cells
Source: NEJM

10. • Mutations in AIRE gene.
• Absence of regulatory T cells.
• Auto reactive T cells escape removal
• These cells then act on the auto antigens which
leads to disease in various organs.
10
APS1 cont’d

11. 11
APS1 cont’d
Mutations
• Finnish major
mutation (p.R257X).
• 13 base pair deletion
in histone proteins.
Autoantibodies
NALP5
GAD65
21 hydroxylase
Type 1 Interferon
Source: NEJM

12. 12
Autoimmune polyglandular
syndrome type 2
• More common
• Women predominate.
• Onset - young adult hood.
• Diagnosis - clinical features and autoantibodies
identification.

13. • Celiac disease
• Alopecia
• Vitiligo
• Primary ovarian
insufficiency
• Pernicious
anemia.
13
APS2 cont’d
Cardinal components
Type 1 diabetes Mellitus
Hypothyroidism
Addison’s disease
Other features

14. • Polygenic- MHC etc
• DR3-DQ2, DR4-DQ8
• Antibodies against TPO, GAD65, 21 hydroxylase
are seen.
14
APS2 cont’d
Genetics and mechanisms

15. 15
Diagnostic
evaluation
Source: NEJM

16. IPEX
• X linked
• Polyendocrinopathy
• Enteropathy
• Early onset type 1 diabetes Mellitus.
• Classically presents in infancy.
16

17. 17
IPEX cont’d

18. 18
Cardinal components
Life threatening chronic diarrhoea
Autoimmune endocrinopathy (type 1
DM or thyroiditis)
Dermatitis
IPEX cont’d
Other features
Immune related
cytopenia.
Nephritis
Hyper reactivation of
immune system to
infections
Allergic airway disease.
Source: NEJM

19. 19
Mutations
FOXP3 gene mutations
IPEX cont’d
Other manifestations
Gastrointestinal
Endocrinopathies (diabetes m/c,
thyroiditis, hypoadrenalism, growth
hormone deficiency)
Haematological disorders (haemolytic
anemia’s, thrombocytopenia,
neutropenia)
Sepsis (enterococcal, staphylococcal,
cytomegalovirus, Candida)

20. 20
IPEX cont’d
Lab
evaluation

21. 21
Source: NEJM

22. Management
Outline
• General management
• Hormone replacement
• Patient education
24

23. Mucocutaneous candidiasis
25
General management
Antifungals
Topical antifungals (clotrimazole oral paste)
Oral antifungals (fluconazole, ketoconazole)
Fluconazole: Oral: Loading dose of 200 mg on day 1, then
100 to 200 mg once daily for 7 to 14 days; recommended for
patients unresponsive to topical therapy or those with moderate to
severe infection
Source: medscape

24. 26
Management cont’d
Hypoparathyroidism
Source: UpToDate

25. 27
Type 1 Diabetes Mellitus
HbA1c targets in most adults is 7% and 7.5% in
children and adolescents (ADA).
Target glucose range is 70- 180mg/dL
Insulin replacement goal- intensive regimen.
Meal time bonuses of rapid acting insulin.
Management cont’d

26. 28
Source: uptodate

27. • Modified intensive regimen: offers benefit of
fewer injections during school hours and flexibility
around meals while at home.
• This includes NPH + rapid acting insulin at
breakfast. Insulin glargine or detemir with dose
of rapid acting insulin at dinner.
• This regimen avoids need of lunch time dose of
insulin.
29
Management cont’d

28. • Intensive insulin regimen: closely approaches
physiologic insulin secretion.
• Basal insulin + with premeal and presnack
boluses of rapid acting insulin.
• Intensive insulin regimen showed better results in
adults.*
*In adults DCCT (diabetes control and complication trial) demonstrated intensive insulin therapy achieved better glycemic
control and reduced long term sequelae.
30
Management cont’d
Source: UpToDate

29. Investigational therapies for type 1 diabetes
Mellitus in children.
Diabetes prevention- trials of vaccine against GAD,
Rituximab, teplizumab.
Artificial pancreas.
Adjunctive therapies- pramlintide- most promising.
Transplantation- limited to adults.
31
Management cont’d

30. Thyroiditis
Hyperthyroid phase- symptomatic treatment.
propranolol 40-120 mg daily
atenolol 25 to 50 daily
Thyroid function should be monitored every 4 to 8
weeks.
Glucocorticoids can be used in severe cases.
32
Management cont’d

31. Hypothyroid phase-
Treat when TSH exceeds 10mU/L, even in absence of
symptoms.
Usual dose of T4 is 50 to 100 mcg daily.
Thyroid levels are monitored every 4 to 6 weeks.
33
Management cont’d

32. Autoimmune enteropathy (IPEX)
34
Management cont’d
Acute management
Correcting electrolyte derangement and hydration
Treating infections
Isolation to prevent nosocomial infections
Immunesuppression
Source: UpToDate

33. 35
Management cont’d
Long term management
Intensive immune suppression (high dose prednisolone)
Steroid sparing agents- tacrolimus, cyclosporine, sirolimus.
Nutrition- extensively formalised feeds to reduce exposure to allergens.
Replacing vitamins and minerals.
Avoidance of vaccination- these can trigger fatal flares (IPEX)
Hematopoetic stem cell transplantation
Source: UpToDate

34. Pernicious anemia
Replacement with cyanocobalamin is the goal of
therapy.
1 mg IM once a day for 7 days, and then weekly for 1-2
months or until the hemoglobin is normalized. Long-
term therapy is 1 mg/mo.
Correction of hypokalemia.
36
Management cont’d
Source: medscape

35. • Thyroid hormone replacement.
• premature ovarian failure
OCP till the age of 50 to 51 years to all
women with POI to manage estrogen
deficiency symptoms, prevent long
term risks.
37
Management cont’d
Hormone replacement

36. • Estrogen-progesterone hormone therapy-
transdermal estradiol (100mcg daily) or estradiol
vaginal ring (100 mcg daily).
• Young women - low doses.
38
Management cont’d
Source: UpToDate

37. • Progestin- first line progestin is micronised
progesterone 200 mg per day for first 12 days of
month.
• MPA (10 mg daily for 12 days per calendar
month).
• Exogenous gonadotropin is ineffective.
• IVF with donor oocytes.
39
Management cont’d
Source: UpToDate

38. 40
Oral capsule: Testosterone undecanoate:
Initial: 237 mg twice daily. Dosage range: 158 to 396 mg twice daily.
Pellet (for subcutaneous implantation): 150 to 450 mg every 3 to 6 months.
SubQ (testosterone enanthate): Initial: 75 mg once weekly. Dosage range:
50 to 100 mg once weekly.
Testosterone replacement
Source: UpToDate

39. 41
Buccal: 30 mg twice daily (every 12 hours) applied to the gum region above
the incisor tooth.
IM (testosterone enanthate or testosterone cypionate):
Initial: 75 to 100 mg/week or 150 to 200 mg every 2 weeks; dosage range: 50
to 100 mg/week or 100 to 200 mg every 2 weeks (AUA [Mulhall 2018];
Endocrine Society [Bhasin 2018]).
IM (testosterone undecanoate): Initial: 750 mg, followed by 750 mg
administered 4 weeks later, then 750 mg administered every 10 weeks
thereafter.
Management cont’d
Source: UpToDate

40. Replace steroids: ~15–25mg hydrocortisone daily,
2 –3 doses, eg: 10mg on waking, 5mg lunchtime.
Avoid giving late (may cause insomnia).
Mineralocorticoids to correct postural hypotension, Na+,
K+: fludrocortisone PO from 50–200mcg daily.
42
Adrenal insufficiency
Management cont’d

41. 43
Management cont’d
Adrenal crisis

42. Asplenia vaccination and antibiotic prophylaxis
Recommended vaccines
• 13-valent pneumococcal conjugate vaccine (PCV13)
• 23-valent pneumococcal polysaccharide vaccine (PPSV23)
• H. influenzae type b vaccine (Hib)
• Quadrivalent meningococcal conjugate ACWY vaccine series
(MenACWY)
• Monovalent meningococcal serogroup B vaccine series (MenB-4C
or MenB-FHbp)
44
Management cont’d

43. 45
Vaccination schedule
Management cont’d
Source: UpToDate

44. Immunocompromising conditions (eg, hematologic malignancy, hypogammaglobulinemia, solid organ transplantation, advanced liver
disease, or HIV infection)
46
antibiotic prophylaxis
Management cont’d
Daily antibiotic prophylaxis until age 5 and for at least one year.
Immunocompromised - at least 18 yrs or until immunocompromised
status or lifelong.
history of sepsis or other severe infections caused by encapsulated
organisms (eg, S. pneumoniae), - lifelong prophylaxis.
adults- daily antibiotic prophylaxis for at least one year.
Source: UpToDate

45. 47
antibiotic prophylaxis - cont’d
Management cont’d
Source: UpToDate

46. Outpatient management should include patient education on the
various components of polyglandular autoimmune (PGA)
syndrome, and the need to screen close relatives as appropriate.
An important aspect of patient education is the provision of
information about adrenal deficiency; subtle deficiency that goes
unnoticed in normal, daily-life situations may become life-
threatening in stressful situations.
48
Patient education

47. Because multiple components of the syndrome
can appear asynchronously, periodic
evaluation for the early appearance of
additional disease components is indicated.
49
Source: Oxford handbook of clinical medicine.

48. 50
Thank you