Deep vein thrombosis, an unreported first manifestation of polyglandular autoimmune syndrome type III.

A 71-year-old woman with severe right lower leg pain, edema and erythema was presented to the Emergency Department and was found to have an extensive deep vein thrombosis (DVT) confirmed by ultrasound. She underwent an extensive evaluation due to her prior history of malignancy and new hypercoagulable state, but no evidence of recurrent disease was detected. Further investigation revealed pernicious anemia (PA), confirmed by the presence of a macrocytic anemia (MCV=115.8fL/red cell, Hgb=9.0g/dL), decreased serum B12 levels (56pg/mL), with resultant increased methylmalonic acid (5303nmol/L) and hyperhomocysteinemia (131μmol/L), the presumed etiology of the DVT. The patient also suffered from autoimmune thyroid disease (AITD), and both antithyroglobulin and anti-intrinsic factor antibodies were detected. She responded briskly to anticoagulation with heparin and coumadin and treatment of PA with intramuscular vitamin B12 injections. Our case suggests that a DVT secondary to hyperhomocystenemia may represent the first sign of polyglandular autoimmune syndrome III-B (PAS III-B), defined as the coexistent autoimmune conditions AITD and PA. It is important to recognize this clinical entity, as patients may not only require acute treatment with vitamin B12 supplementation and prolonged anticoagulation, as in this patient, but may also harbor other autoimmune diseases. Learning points A DVT can be the first physical manifestation of a polyglandular autoimmune syndrome. Hyperhomocysteinemia secondary to pernicious anemia should be considered as an etiology of an unprovoked DVT in a euthyroid patient with autoimmune thyroid disease. Patients with DVT secondary to hyperhomocysteinemia should undergo screening for the presence of co-existent autoimmune diseases in addition to treatment with B12 supplementation and anticoagulation to prevent recurrent thromboembolism. Introduction Polyglandular autoimmune syndromes (PASs) are a heterogenous group of uncommon diseases defined by the presence of autoantibodies targeting two or more organ systems. Pernicious anemia (PA) was first described in the mid nineteenth century by Thomas Addison who recognized an association between adrenocortical failure and PA (1, 2). PASs were originally classified into two major types by Neufeld (3) and later extended into three by Eisenbarth and Gottlieb (4, 5). PAS I, also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), involves the presence of two or more of the following three pathologies: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison’s disease, which tends to present in pediatric patients in the order listed. PAS II, also known as Schmidt’s syndrome, is more common than PAS I and is defined by the presence of Addison’s disease with either autoimmune thyroid disease (AITD) or type 1 diabetes mellitus. PAS III, considered a subtype of PAS II, presents with AITD and one or more other organ-specific autoimmune disease(s), most commonly involving the pancreas, stomach, intestine or skin; the adrenal and parathyroid glands are uninvolved (5, 6). One common association of AITD is pernicious anemia, defined as anemia caused by vitamin B12 deficiency resulting from autoantibodies targeting the source of intrinsic factor, the parietal cells of the stomach or intrinsic factor itself (7). Vitamin B12 is an essential cofactor in the metabolism of both amino acids and fatty acids (7). Therefore, B12 deficiency can lead to decreased assembly of products necessary for myelination of the corticospinal tracts and the dorsal columns of the spinal cord, a condition known as subacute combined degeneration of the spinal cord, as well as toxic accumulation of metabolic precursors such as homocysteine (8). Hyperhomocysteinemia (HH) has been established as an independent risk factor for cardiovascular disease in causing both atherosclerosis and deep venous thrombosis (DVT) (9). We report a patient diagnosed with PAS III-B after presenting with a DVT, a previously unreported initial manifestation of the disease.