APS case based approach

1. AUTOIMMUNE POLYENDOCRINE
SYNDROMES
MODERATOR-Dr SRIKANTH

2. OUTLINE
 INTRODUCTION
 CLINICAL SCENARIO 1
 APS 1
 CLINICAL CASE SCENARIO 2
 APS 2
 SUMMARY

3.  Autoimmune polyendocrine syndromes (APSs), also called autoimmune
polyglandular syndromes (APSs), polyglandular autoimmune syndromes
(PGASs),or polyendocrine autoimmune syndromes, are a heterogeneous
group of rare diseases characterized by autoimmune activity against more
than one endocrine organ
 Importantly,there are many nonendocrine disease associations included in
thesesyndromes, suggesting that although the underlying autoimmune
disorder predominantly involves endocrine targets, it does not exclude
other tissues.

4. AUTOIMMUNE POLYENDOCRINE SYNDROME
APS TYPE 1 APS TYPE 2

5. CLINICAL SCENARIO 1
A 16 year old female,student, presented with the chief complaints of
Multiples white patches over nails and tongue since 5 years of age
Easy fatiguability and lightheadedness since 6 months
Numbness and tingling sensation in the fingers and toes since 1 month

6.  HISTORY OF PRESENT ILLNESS
The patient was apparently normal until the age of 5 years when during a regular health
checkup she was noted to have a white patch over the tongue. According to the patients mother
the patient was told to have a fungal infection and was treated with oral medication and mouth
wash.
Since then the patient reports to have recurrent episodes such white patches over the
tongue.No h/o pain/bleeding .No h/o pain on swallowing.She also noticed whitish patches over
the webspaces of the toes and has also noticed curdy white discharge PV associated with
burning micturition
She also gives h/o easy fatiguability since 6 months.She feels tired even on carrying out day to
day activities.Patient also feels lightheaded,especially on getting up from lying down position.No
h/o chest pain/palpitations/orthopnea/PND.No h/o hearing loss/tinnitus
She complains of tingling numbness over bilateral toes and fingers since 1 month.No h/o any
motor weakness.
No h/o polyuria/polydipsia.
Patient gives h/o frequent episodes of nausea and h/o weight loss of approximately 5kg over the
last 6 months.
No h/o chronic diarrhea.No h/o blood in stools.No h/o fever.

7.  Past history-Patient is a k/c/o of hypothyroidism on L-thyroxine 50mcg.
 Personal history-mixed diet,bowel and bladder habits normal.No addictions.
 Family history-parents have had a consanguineous marriage (3rd degree).No h/o similar
complaints in the family.
 Menstrual history-patient has not attained menarche.
GENERAL EXAMINATION
Patient is conscious,co-operative well oriented to time place person.Moderately built and
nourished
BP-100/60mmHg in rt arm supine position PR-86bpm.
78/50mm Hg on standing(after 1 min) RR-18cpm GRBS-86mg/dl
Pallor present.No icterus,cyanosis,clubbing.No cervical/axillary/inguinal lymphadenopathy

8. ON elevating the BP cuff pressure to 10mm Hg
above the systolic pressure for 1 min the
following observed:

9. INVESTIGATIONS

10. APS 1
 Autoimmune polyendocrine syndrome type I is an autoimmune syndrome
with characteristic disease associations, that often appear early in life,
typically in infants with persistent candidal infection of the skin and
mucous membranes without the systemic infection generally associated
with severe immunodeficiency
 APS-1 has also been called autoimmune polyendocrinopathy–candidiasis–
ectodermal dystrophy (APECED)
MUCOCUTANEOUS CANDIDIASIS
WHITAKERS
TRIAD
HYPOPARATHYROIDISM
ADRENAL INSUFFICIENCY

11.  Other endocrine disorders that occur less frequently include
 type 1diabetes (23%) and autoimmune thyroid disease (18%).
 Nonendocrine manifestations that present less frequently include alopecia
(40%), vitiligo(26%), intestinal malabsorption (18%), pernicious anemia
(31%),chronic active hepatitis (17%).

12. ETIOPATHOGENESIS
 It is an autosomal recessive disorder caused by mutations in the AIRE gene
(autoimmuneregulator gene) found on chromosome 21
 This gene is most highly expressed in thymic medullary epithelial cells (mTECs)
where it appears to control the expression of tissue-specific self-
antigens.Deletion of this regulator leads to decreased expression of tissue-
specific self-antigens and is hypothesized to allow autoreactive T cells to avoid
clonal deletion, which normally occurs during .T cell maturation in the thymus.

14. CLINICAL FEATURES
 The first manifestation usually occurs in childhood, and the complete evolution of the 3
main diseases takes place within the first 20 years of life. Accompanying diseases continue to
appear at least until the fifth decade of life.
 Candidiasis usually is the first clinical manifestation, most often presenting in people younger
than 5 years. Hypoparathyroidism occurs next, usually in people younger than 10 years. Lastly,
Addison disease occurs in people younger than 15 years.
 Mucocutaneous candidiasis
-This condition usually occurs earliest and is the most common of the 3 main diseases of PGA-I.
-Between 50 and 100% of patients with PGA-I develop a recurrent monilial infection. Most of the
lesions are limited to the skin (usually < 5% of surface area), nails, and oral and anal mucosa.
Esophageal involvement may be complicated by strictures and stenosis.
-Even though the presence of candidiasis is consistent with a T-cell defect, no increased frequency
of other opportunistic infections exists.

15.  Hypoparathyroidism [
 This is the first endocrine disease to occur during the course of PGA-I, usually
developing after candidiasis and before Addison disease.
 Antiparathyroid antibodies have been reported in 10-40% of patients with
hypoparathyroidism; however, whether these are being confused with mitochondrial
autoantibodies is still under debate. The pathologic significance of these antibodies is
not clear.
 Other disease states presenting with neonatal hypocalcemia (DiGeorge syndrome or
congenital absence or malformation of the parathyroid) must be differentiated from
PGA-I. DiGeorge syndrome results from a congenital defective disorder of the
branchial clefts. It manifests as hypoparathyroidism and cutaneous candidiasis; unlike
PGA-I, DiGeorge syndrome does not involve the adrenal glands.
 More than 75% of patients develop hypoparathyroidism, which usually presents in
persons younger than 10 years.
 Clinical features may include, among others, (1) tetanic clinical symptoms, such as
carpopedal spasm and paresthesias of the lips, fingers, and feet; (2) seizures; (3)
laryngospasm; (4) leg cramps; (5) diffuse mild encephalopathy; (6) cataracts.
Electrocardiography may show a prolonged QT interval.

16.  Adrenocortical failure (Addison disease)
 Addison disease typically occurs in people aged 10-30 years (mean, 12-13 y); it
usually is the third disease to appear in PGA-I.
 Mineralocorticoid and glucocorticoid deficiencies usually arise simultaneously, but
their onset can be dissociated by up to 3 years.
 Early symptoms include weakness, fatigue, and orthostatic hypotension.
 Pigmentation usually is increased and may serve as a differentiating point from
secondary hypoadrenalism (primary pituitary failure).
 Anorexia, nausea, vomiting, diarrhea, and cold intolerance often occur.
 Late symptoms include weight loss, dehydration, hypotension, and a small-sized
heart.

17.  Less common clinical manifestations
 Hypergonadotropic hypogonadism (primary hypogonadism)
 Type 1 diabetes mellitus
 Autoimmune thyroid disease (not including Graves disease)
 Pernicious anemia
 Chronic atrophic gastritis
 Chronic active hepatitis
 Enamel hypoplasia, which occasionally precedes the onset of hypoparathyroidism
 Asplenia
 Keratoconjunctivitis
 Cholelithiasis
 Malabsorption
 Alopecia
 Vitiligo
 Interstitial nephritis
 Pure red cell aplasia

18. INVESTIGATIONS

19. TREATMENT
 ENDOCRINOPATHIES-HORMONE REPLACEMENT
-replacement therapy with thyroid hormone can precipitate an
adrenal crisis in an undiagnosed individual. Hence, all patients with
hypothyroidism and the possibility of APS should be screened for adrenal
insufficiency to allow treatment with glucocorticoids prior to the initiation of
thyroid hormone replacement
 Mucocutaneous candidiasis must be treated aggressively and monitored
for recurrence
-antifungal agents should be started at presentation
- anywhere along GI tract
-if left untreated -- squamous cell carcinoma of the oral cavity
or esophagus

20. TREATMENT
 If asplenism is identified, vaccinations against
- Streptococcus pneumoniae (pneumococcus)
-Neisseria meningitides (meningococcus) and
- Hemophilus influenzae
 HYPOPARATHYROIDISM-Calcium and Vit D supplementation
 IMMUNOSUPRESSIVES

21. CLINICAL CASE SCENARIO 2
 A 30 year old male,farmer by occupation,was brought the casualty with history of
giddiness,palpitations and sweating over the past 1 hour
 GRBS was found to be 61mg/dl.He was managed conservatively with 25% dextrose following
which his condition improved.
 He was a known type 1 DM patient on twice daily premixed insulin therapy for the last 4 years.
For the last few months, he was having recurrent attacks of hypoglycemia requiring his
physician to lower the dose of insulin.
 On further inquiry, he also gave history of generalized weakness, easy fatigability, postural
dizziness, gradual darkening of skin and tongue for the last 6 months.
 The patient denied any history of diarrhea, weight loss, or loss of libido. No history of similar
illness in the family was given.

22.  On further examination, there was generalized darkening of skin along
with hyperpigmented patches noted on his elbows, palms, knuckles of
hands, soles, tongue, oral mucosa including the palates (Fig. 1A, B, C).
Thyroid gland was palpable. Secondary sexual characteristics were well
developed.

24. APS 2
 APS-2 is more common than APS-1 with a prevalence of 1 in 100,000.
 It occurs more often in female patients with a ratio of at least 3:1 compared to male
patients.
 In contrast to APS-1, APS-2 often has its onset in adulthood with a peak incidence between
20 and 60 years of age
 It shows a familial multigenerational inheritance.
PRIMARY ADRENAL
INSUFFICIENCY
GRAVES DISEASE OR AUTOIMMUNE
THYROIDITIS
TYPE 1 DIABETES
MELLITUS
PRIMARY HYPOGONADISM
2 OR MORE OF THE
FOLLOWING

25. ETIOPATHOGENESIS
 Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both
HLA-DR3 and HLA-DR4.
 Other class I and class II genes and alleles, such as HLA-B8,HLA-DQ2 and HLA-DQ8, and
HLA-DR subtype such as DRB1*0404,appear to contribute to organ-specific disease
susceptibility
 HLA-B8- and HLA-DR3-associated illnesses include selective IgA deficiency, juvenile
dermatomyositis, dermatitis herpetiformis, alopecia,scleroderma, autoimmune
thrombocytopenia purpura, hypophysitis,metaphyseal osteopenia, and serositis.

26. CLINICAL FEATURES
 Type 1 diabetes mellitus,
Symptoms - Polyuria, polydipsia, polyphagia, unexplained weight loss, intermittent blurred vision, and
lethargy (may present initially with diabetic ketoacidosis and coma)
Signs - Depend on the severity; consist of poor skin turgor, orthostasis, and hypotension
 Hashimoto thyroiditis (chronic lymphocytic thyroiditis)
Symptoms - Usually nonspecific and include cold intolerance, fatigue, somnolence, poor memory,
constipation, menorrhagia, myalgias, and hoarseness
Signs - Slow tendon reflexes, bradycardia, facial and periorbital edema, dry skin and nonpitting edema,
carpal tunnel syndromes, deafness, and pericardial or pleural effusions
 For Graves disease,
Symptoms - Heat intolerance, weight loss, weakness, palpitations, oligomenorrhea, and anxiety
Signs - Brisk tendon reflexes, fine tremor, proximal weakness, stare and eyelid lag, exophthalmos, atrial
fibrillation, and sinus tachycardia
 For Addison disease (primary adrenal insufficiency),
Symptoms - Anorexia, nausea, vomiting, weight loss, weakness, and fatigue
Signs - Chronic hyperpigmentation of creases and scars, as well as orthostatic hypotension

27. INVESTIGATIONS

28. TREATMENT
 With the exception of Graves’ disease, the management of each of the endocrine
components of APS-2 involves hormone replacement
 Hashimoto thyroiditis (Hashimoto disease),
-Treatment of hypothyroidism remains independent of its cause. The aim is to achieve
euthyroidism.
-Comorbidity (cardiac disease and advanced age) necessitates smaller initial doses, usually
12.5-25 mcg/d. This view has been questioned by some.
-States such as pregnancy and younger healthy people require maintenance doses,
approximately 75-125 mcg/d (1.6 mcg/kg/d).
Thyroid-stimulating hormone (TSH) is used to assess the level of euthyroidism. After 6 weeks
of therapy, measure plasma TSH. Adjust the dose in increments of 12-25 mcg at intervals of
6-8 weeks until TSH is normal. Thereafter, annual measurements can be taken to ensure
compliance and prevent overtreatment.

29.  type 1 diabetes mellitus
-It requires lifelong treatment with exogenous insulin.
-A roughly estimated dose for otherwise healthy individuals is approximately 0.6-1.2
U/kg/d (35-50 U/d in adults).
-Various dosage regimens and types of insulin exist. The ultimate goal of treatment is to
achieve persistent normoglycemia with a minimum of hypoglycemic complications.
 pernicious anemia
-Replacement with cyanocobalamin is the goal of therapy.
-A typical schedule is 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.
-Symptomatic hypokalemia may occur within 48 hours of initiating therapy, and
supplemental potassium may be needed.
-With therapy, the reticulocytosis should rise and peak in 1 week, followed by a rising
hemoglobin level in the next 6-8 weeks.

30.  Addison disease
 Adrenal insufficiency requires replacement therapy with hydrocortisone and
fludrocortisone.
 Adjust the hydrocortisone dose depending on patient's symptoms. Monitor the activity
levels of plasma renin to assess the efficacy of treatment with fludrocortisone and serum
electrolytes.
 In case of concurrent illness, increase the doses of hydrocortisone.
 In the presence of coexisting diabetes, occasionally seen in polyglandular autoimmune
syndrome type I, the daily dose usually should not exceed 30 mg/d because this
necessitates higher doses of insulin, and on many occasions, there is difficulty in
controlling glucose levels

31. SUMMARY

32.  THANK YOU