OR19-4 High Prevalence of Primary Hypothyroidism in Patients with Alkaptonuria Eighteen Years of Experience

Background: Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by pathogenic variants in the gene encoding homogentisate-1,2-deoxygenase (HGD). Deficiency of HGD leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies, aortic and mitral valve degeneration and kidney stones. HGD is vital for the catabolism of tyrosine, which provides the backbone of iodination into thyroxine (T4) within the thyroid gland. The goal of this study was to assess thyroid function (TFT) in patients (pts) with AKU. Methods: We performed a cohort study including pts with AKU followed at our center between 2000 and 2018. All pts had thyroid stimulation hormone (TSH), freeT4 (fT4), anti-thyroid peroxidase antibodies (anti-TPO-abs) measured repeatedly by immunoassay. In addition, a subset of patients underwent a thyroid ultrasound (US). Hypothyroidism (HYPO) was defined as TSH above the reference range (0.27-4.2 mIU/ml) with fT4 below the reference range (0.9-1.7 ng/dl) on two repeated tests or normalization of TSH on levothyroxine (LT4) replacement therapy. Subclinical HYPO (S-HYPO) was defined as TSH above the reference range with normal fT4 on two repeated tests. Results:The study cohort consisted of 130 pts with AKU, majority men (55.4%), aged 59.1±15 years and followed for 36 (range 1-63) months, during which median 10 (range 2-35) TFTs were performed. Twenty-four pts were diagnosed with HYPO, but 3 pts were excluded due to post-thyroidectomy etiology of HYPO, giving a prevalence of HYPO of 16.5% (21/127) - significantly higher than reported 5% of the general population (p=0.006). S-HYPO was diagnosed in 4.7% (6/127) and overt HYPO in 11.8% (15/127) pts, who were treated with a median LT4 dose of 100 mcg daily (1.4 mcg/kg). The median thyroid volume in HYPO pts was 7 cc (range 3.9-13). The prevalence of elevated anti-TPO-abs in the whole cohort was 14% (18/127), while its prevalence in HYPO group was 43% (9/21) - significantly lower than reported 89.8% for HYPO pts in the general population (p<0.001). Among 49 pts who had thyroid US performed, thyroid nodules with a median size of 0.4 (range 0.3-3.2) cm were identified in 59.2% (29/49), similar to prevalence observed in general population (p=0.63). Three pts (6%) were diagnosed with thyroid cancer (TC), 2 - with micro-papillary TC and 1 with Hurthle cell TC. The prevalence of TC was similar to prevalence observed in general population (p=0.77). Conclusions: AKU is associated with high prevalence of primary HYPO. The etiology of HYPO is unclear, given low prevalence of anti-TPO-abs in hypothyroid AKU pts. Further functional studies are needed to assess potential pathologic effect of the accumulation of HGA on thyroid hormone synthesis and function.