Sandbox:Akshun

polyglandular autoimmune syndrome polyendocrine autoimmune syndrome

tryptophan hydroxylase presenting with malabsorption

• • • Tyrosine hydroxylase presenting with alopecia areata
    • Liver presenting with autoimmune liver disease and chronic active hepatitis
    • Steroidal hormone–producing cell presenting with hypogonadism.

X linked polyendocrinopathy, immune dysfunction and diarrhea. This condition is very rare and generally presents in neonatal period with diabetes and malabsorption. Unlike type 1 and type 2 autoimmune polyglandular syndromes there is no association with HLA genotype. Mutation in FOXP3 gene is inherited as X linked and leads to loss of regulatory T cells and autoimmunity.

The term “polyendocrine” itself is a misnomer, in that not all patients have multiple endocrine disorders, and many have nonendocrine autoimmune diseases. Nevertheless, the recognition that patients in whom multiple autoimmune disorders are diagnosed may have a specific genetic syndrome, may be at increased risk for multiple autoimmune disorders, and may have relatives who have an increased risk should spur clinicians toward early diagnosis and treatment.

In the simplest hypothesis for understanding organ-specific autoimmunity, the initial step is the loss of immunologic tolerance to a peptide within a specific molecule found in the target organ. Clones of the CD4 T cells that recognize the peptide then expand, and the specific cytokines produced by the clonal CD4 T cells favor inflammation (as when type 1 helper T [Th1]–cell clones produce cytokines such as interferon-γ) or favor autoantibody-mediated disease (as is the case predominantly with type 2 helper T [Th2]–cell clones).9 The probability of T-cell autoreactivity is determined both in the thymus (the site of central tolerance) and in the periphery (the site of peripheral tolerance) and is strongly influenced by specific HLA alleles

TYPE 1 APS Mutations in the AIRE gene cause many autoimmune diseases, and affected patients are at risk for the development of multiple additional autoimmune diseases over time, including type 1A diabetes, hypothyroidism, pernicious anemia, alopecia, vitiligo, hepatitis, ovarian atrophy, and keratitis. Affected patients may also have diarrhea or obstipation that may be related to the destruction of gastrointestinal endocrine cells (enterochromaffin and enterochromaffin-like cells).39 Knockout of the AIRE gene in the mouse produces widespread autoimmunity, but the phenotype is relatively mild

Aldosterone Deficiency: Hyporeninemic hypoaldosteronism - Commonly seen in patients with renal insufficiency (diabetic kidney disease, chronic tubulointerstitial disease, or glomerulonephritis) and those that take certain medications (non-steroidal anti-inflammatory drugs, calcineurin inhibitors).[1] Angiotensin inhibitors - angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibitors Heparin therapy (including low molecular weight heparin) - Heparin has a direct toxic effect on the adrenal zona glomerulosa cells which leads to a reduction in plasma aldosterone concentration.[9] Primary adrenal insufficiency (Addison’s disease) - Associated with the lack of cortisol and aldosterone. This can result from autoimmune adrenalitis, infectious adrenalitis, and other disorders.[14] Critical illness - There is decreased adrenal production of aldosterone and stress-induced hypersecretion of ACTH which can diminish aldosterone synthesis by diverting substrate to the production of cortisol. Congenital isolated hypoaldosteronism - Deficiency of enzymes required for aldosterone synthesis.[14] Pseudohypoaldosteronism type 2 (Gordon’s syndrome or familial hyperkalemic hypertension) - Abnormalities in WNK kinases in the distal nephron increase chloride reabsorption leading to reduced renal potassium secretion. Characterized by hypertension, hyperkalemia, metabolic acidosis, normal renal function, and low or low-normal plasma renin activity and aldosterone concentrations.[14][2] Aldosterone Resistance: Inhibitors of the epithelial sodium channel - Most commonly associated with the administation of potassium-sparing diuretics (spironolactone, eplerenone, amiloride) and certain antibiotics (trimethoprim, pentamidine). Pseudohypoaldosteronism type 1 - Characterized by marked elevations of plasma aldosterone levels. There is an autosomal recessive form, and an autosomal dominant or sporadic form. The autosomal dominant form tends to be associated with milder symptoms

Type of Adrenal insufficiency	Skin Pigmentation	ACTH	Normal ACTH
Addison disease	+	>60 ng/mL	5-30 ng/mL
Secondary / tertiary adrenal insufficiency	-	<5 ng/mL

Addison's disease must be differentiated from other diseases that cause hypotension, skin pigmentation, and abdominal pain such as myopathies, celiac disease, Peutz-Jeghers syndrome ,anorexia nervosa, syndrome of inappropriate anti-diuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.

Disease	Differentiating symptoms							Differentiating laboratory findings			Gold standard test
	Hypotension	Abdominal pain	Anorexia/ weight loss	Muscle weakness	Hypoglycemia	Skin pigmentation	Other symptoms	Hyponatremia	Cortisol levels	Other labs
Addison's disease	+	+	+	+	+	+		-	Low		ACTH stimulation test
Myopathies (polymyositis, hereditary myopathies)	-	-	-	+	-	Heliotrope rash and Gottron's sign	Muscle tenderness	-	Normal	-	Muscle biopsy
Celiac disease	-	+	+	-	-	Dermatitis herpetiformis	Greasy stools Increased fecal fat	-	Normal	-	Abnormal small bowel biopsy
Syndrome of inappropriate anti-diuretic hormone (SIADH)	-	-	-	-	-	-	-	+	Normal	Decreased osmolality Euvolemia Sodium in urine typically >20 mEq/L	Water deprivation test
Neurofibromatosis	-	-	+	+	-	Axillary- and inguinal-area freckling	Occasional development of peripheral sarcomas May have overgrowth of subcutaneous tissues	-	-	-	Biopsy of skin tissue
Peutz-Jeghers syndrome		+				+	Melanotic hyperpigmentation of the skin and mucous membranes	-	Normal		Colonic imaging showing the small intestinal polyps
Porphyria cutanea tarda	-	+	-	-	-	Blisters on sun-exposed sites	Associated liver disease (usually hepatitis C) Hypertrichosis	-	Normal or elevated	High level of porphyrins in the urine
Salt-depletion nephritis	+	Flank pain	-	-	-	-	Fever Dysuria Pyuria Oliguria	+	Elevated	<15:1 BUN:CR
Bronchogenic carcinoma	-	-	+	-	-	+	Cough Dyspnea Hemoptysis	-	Elevated	Increased ACTH and Hypokalemia	Cytological or histological evidence of lung cancer in sputum, pleural fluid, or tissue
Anorexia nervosa	+	-	+	+	+	-	Distorted body image Oligomenorrhea	-	Elevated	-	Psychiatric condition