Autoimmune Polyglandular Syndromes: Immune and Hormonal Dysfunctions

What Are Autoimmune Polyglandular Syndromes?

Autoimmune polyglandular syndromes (APS) are a group of endocrine aberrations that occur in discrete patterns in patients with immune dysfunction along with associated systemic or hormonal deficiencies. Autoimmune polyglandular syndromes present with immune dysregulations (immune system problems), polyendocrinopathies (problems in multiple endocrine glands), and enteropathies (intestinal disorders), especially in patients treated with immunoregulatory agents for cancer.

What Are the Types of Autoimmune Polyglandular Syndromes?

The type of autoimmune polyglandular syndromes are:

• Autoimmune polyglandular syndromes-I (APS-1).

• Autoimmune polyglandular syndromes-II (APS-2).

• Autoimmune polyglandular syndromes-III (APS-3).

• X-linked APS (immuno-dysregulation polyendocrinopathy enteropathy X-linked or IPEX).

APS-3 is further classified into three distinctive variants:

• APS3A – Autoimmune thyroiditis with immune-mediated diabetes mellitus (a metabolic condition that causes elevated blood sugar levels).

• APS3B – Autoimmune thyroiditis with pernicious anemia (lack of red blood cells).

• APS3C – Autoimmune thyroiditis with vitiligo (patchy loss of skin color) or alopecia (hair loss), or other organ-specific autoimmune diseases.

Who Is Susceptible to Autoimmune Polyglandular Syndromes?

APS-1 is a rare autoimmune condition found in populations like the Finns, Iranian Jews, and Sardinians. The incidence stands at 1 in 9000, 1 in 1000, and 1 in 1,45,000 of the ethnicities, respectively. In the US (United States), APS-1 is seen in some ethnic groups with a prevalence of 1 in 2,000,000 to 3,000,000 newborns. APS-2 is more prevalent than APS-1, with a prevalence of 14 to 20 cases per million in the population, with three to four times the female dominance, usually in the ages of 21 to 40 years. APS-3 has reported less than 70 cases worldwide.

What Causes Autoimmune Polyglandular Syndromes?

APS-1 is caused due to a failure to eliminate T-cells triggered against auto-antigens. These T-cells mature and cross the thymic epithelium. Due to the variable expression of the AIRE gene (autoimmune regulator gene) present on chromosome 21, the adaptive immune response cascade is activated, and the spectrum of disorders associated with APS-1 is manifested. Both T and B cell abnormalities are observed in APS-I, which is demonstrated by the presence of steroidogenic or thyroid synthesis cascade enzymes in the serum.

APS-II is caused due to autoimmunity directed against pancreatic β-cell (beta cell), adrenal cortex, and thyroid synthesizing machinery that gives rise to the characteristic features of deficient adreno-cortical and thyroid functions. APS-III is similar, with the absence of adrenal-cortex involvement. Sometimes, APS-II is tagged as APS-2s while APS-III is named APS-2b, the latter being more common than the former. The affected genes for APS II and APS-III are found in the DQ and DR regions of the HLA (human leukocyte antigen) on the short arm of chromosome 6. These mutations, along with the HLA complex, facilitate antigen presentation to dendritic cells and macrophages (cells of immunity). Auto-immunity action is activated due to the presentation of self-antigens and decreases T-regulatory cell expression.

IPEX syndrome (X-linked immune dysregulation polyendocrinopathy enteropathy) is an X chromosome-linked recessive variant of APS due to the FOXP3 (forkhead box3) gene present in location Xp11.13. The gene mutation results in a defect in Treg production that develops reduced amounts of circulating CD4+ (cluster of differentiation 4), CD25+, or FOXP3+.

What Are the Signs and Symptoms of Autoimmune Polyglandular Syndromes?

The autoimmune polyglandular syndrome-I is characterized by the following:

• Mucocutaneous candidiasis (fungal infection).

• Hypoparathyroidism (decreased parathormone levels).

• Hypocalcemia hyperphosphatemia (acute hypocalcemia secondary to hyperphosphatemia).

• Low PTH (parathyroid hormone) concentrations.

• Addison's disease with cortisol deficiency.

• Aldosterone deficiency.

• Elevated adrenocorticotropic hormone.

• Hyperpigmentation.

• Abdominal pain.

• Vomiting.

• Weight loss.

• Electrolyte disturbances.

• Hypoglycemia with fasting (decreased blood sugar levels during fasting).

• Fever.

• Kerato-conjunctivitis (inflammation of the conjunctiva and the superficial cornea).

• Chronic diarrhea.

• Primary gonadal failure (ovarian or testicular failure).

• Hashimoto thyroiditis (autoimmune thyroid disorder).

• Hypothyroidism (underactive thyroid gland).

• Vitamin B12 deficiency.

• Chronic active hepatitis.

• T1DM (type-1 diabetes mellitus).

• Enamel hypoplasia (defect in enamel formation).

• Pitted nail dystrophy (dents in the nails).

• Alterations in the tympanic membrane (problems in the eardrum).

• Iritis (iris inflammation).

• Optic atrophy (death of ganglions of the optic nerve).

• Keratopathy (damage to the cornea).

• Alopecia (balding).

• Vitiligo (patchy pattern loss of skin color).

• Gastric parietal cell failure (dysfunction of the parietal cells of the gastrointestinal system).

The autoimmune polyglandular syndrome-II is characterized by the following:

• T1DM (type-1 diabetes mellitus).

• Addison disease (condition due to insufficiency of the adrenal gland).

• Thyroid autoimmunity with hypothyroidism.

• Hyperthyroidism.

• Hashimoto thyroiditis.

• Celiac disease (immune system triggered by gluten intake).

• Vitiligo (pathy loss of skin pigmentation).

• Alopecia (balding).

• Myasthenia gravis (skeletal muscle weakness due to autoimmune disorder).

• Pernicious anemia (red blood cell deficiency due to vitamin B12 deficiency).

• IgA deficiency (decreased amounts of immunoglobulin A).

• Hepatitis (liver inflammation).

• Hypogonadism (testes or ovaries produce low sex hormones).

• Nausea.

• Frequent urination.

• Palpitations.

• Weight loss.

• Anorexia (eating disorder due to fear of gaining weight).

• Low blood pressure.

• Myalgias (widespread muscle pain).

• Anemia.

The autoimmune polyglandular syndrome-III is characterized by the following:

• Type 1 diabetes mellitus.

• Thyroid autoimmunity.

• Hypothyroidism.

• X-linked APS (antiphospholipid syndrome).

IPEX syndrome is characterized by:

• Diarrhea.

• Vomiting.

• Gastritis (inflammation in the lining of the gastrointestinal wall).

• Ileus (lack of intestinal muscular contractions).

• Colitis (inflammation in the colon).

• Type 1 diabetes.

• Dermatitis (inflammatory skin reaction).

• Eczematiform (skin plaques and scales).

• Ichthyosiform (colloid membrane on the skin).

• Psoriasiform (skin conditions similar to that in psoriasis).

• Cheilitis (lip inflammation).

• Onychodystrophy (change in shape and color of nails).

• Alopecia.

• Thyroid dysfunction.

• Renal dysfunction.

• Reduced counts of thrombocytes.

• Reduced counts of neutrophils.

• Arthritis (joint inflammation).

• Splenomegaly (enlarged spleen).

• Lymphadenopathy (enlarged lymph nodes).

• Infections.

• Autoimmune hemolytic anemia (autoimmune destruction of red blood cells).

• Food allergy.

How to Diagnose Autoimmune Polyglandular Syndromes?

Along with various clinical presentations of the autoimmune polyglandular syndrome, laboratory diagnosis, endoscopy, CT (computed tomography) scan, and histological studies can be included to diagnose APS.

Laboratory Analysis Presents With:

• Lymphocytic infiltration.

• Antibodies to NALP5.

• Adrenal cytochrome P450 enzyme antibodies.

• GAD65 (glutamic acid decarboxylase) antibodies.

• IA2 antibodies.

• Thyroid peroxidase antibodies.

• Anti-thyroglobulin antibodies.

• Microsomal protein antibodies.

• Parietal cell antibodies.

• Intrinsic factors antibodies.

• BPI (bacterial permeability-increasing protein) fold antibodies.

• Potassium channel regulator antibodies.

• Type-1 interferon antibodies.

• Interleukin antibodies.

• Low ACTH (adrenocorticotropic hormone) concentrations.

• Low cortisol levels.

• Eosinophilia.

• Elevated IgE levels.

How to Treat Autoimmune Polyglandular Syndromes?

The treatment guidelines for APS are based on immune suppression and modulation with glucocorticoids like Prednisone and Cyclosporin; calcineurin inhibitors Tacrolimus and Sirolimus; CD20 inhibitors like Methotrexate, Mycophenolate mofetil, and Rituximab.

Hormonal and vitamin deficiencies should be bridged with supplementary therapies. Anti-candida drugs like Ketoconazole, Cortisol therapy, parental Hydrocortisone administration, diabetic management, and glucocorticoid therapy are added to the regimen pertaining to the respective symptoms. Other non-specific manifestations can be managed with a symptomatic approach. Other therapies include the usage of inhibitors of CTLA4 like Ipilimumab, Nivolumab, Pembrolizumab, and anti-tumor necrosis factor-α (alpha) agents.

What Is the Prognosis of Autoimmune Polyglandular Syndromes?

Patients suffering from APS have an increased risk of death due to possible complications arising from individual symptoms. Early detection of adrenal crisis, hypocalcemia, and sepsis, followed by prompt treatment, can greatly incentivize the prognosis.

What Is the Differential Diagnosis of Autoimmune Polyglandular Syndromes?

• Congenital rubella (a viral infection acquired before birth).

• Hemochromatosis (excess iron storage in the body).

• Kearns-Sayre syndrome (neuromuscular disorder).

• Myotonic dystrophy (progressive muscle wasting and weakness).

• Plasma cell dyscrasia (plasma cell proliferation in the bone marrow).

• Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).

• Thymoma (thymus cancer).

• DiGeorge syndrome (microdeletion on the long arm of chromosome 22).

• WDHA syndrome (watery diarrhea, hypokalemia, and lack of hydrochloric acid in the stomach).

• CD25 deficiency (interleukin-2 receptor alpha deficiency).

• STAT5B deficiency (growth hormone insensitivity with immune dysregulation).

• Severe combined immunodeficiency (disturbed development of functional T cells and B cells ).

• X-linked thrombocytopenia (a bleeding disorder in males).

What Are the Complications of Autoimmune Polyglandular Syndromes?

• Cataracts (cloudy lens of the eyes).

• Laryngospasm (involuntary contracture of the vocal cords).

• Basal ganglial calcification (abnormal deposition of calcium in the basal ganglion).

• Ventricular arrhythmias (the abnormal rhythm of the heart ventricles).

• Renal stones (kidney stones).

• Arrhythmias (abnormal heartbeat).

• Electrolyte imbalance (deviation from normal salt and mineral balance of the body).

• Loss of libido (low sex drive).

• Psychotic illnesses (mental health issues).

• Hypoglycemic spells (periods of low blood sugar levels).

• Gastrointestinal complaints (several problems of the gastrointestinal tract).

• Neuropathies (problems secondary to nerve damage).

• Pernicious anemia.

• Celiac disease (immunity triggered due to gluten consumption).

• Hepatitis (liver inflammation).

• Nephritis (kidney inflammation).

• Pneumonitis (lung inflammation).

• Squamous cell carcinoma (skin cancer).

• Osteoporosis (bone becomes weak and brittle).

Conclusion

APS requires long-term treatment with further outpatient care. The patients require dietary modifications with high content of calcium, fresh fruits and vegetables, and low in simple carbohydrates. The patients should undertake stress management techniques with moderate exercise. Long-term steroid therapy comes with its own set of complications and side effects which needs supplemental care and vigilance. The patient should be advised to wear medical alert bracelets to aid in therapy. Hormone therapies and superficial fungal infections can be managed with antifungal therapy. Restoration of the thymic epithelium with intact immunoregulatory function with stem cell engineering to correct the aberrant immune system should be the ultimate long-term goal that has been achieved with limited success. Further studies into the condition can reveal supplemental therapy regimens.