Abstract
Background: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs, including the endocrine system. While endocrine involvement in ECD is well characterized, infiltration of the hypothalamic-pituitary-thyroid axis may cause either primary or central hypothyroidism that is often underdiagnosed. The prevalence of hypothyroidism and the occurrence of isolated central hypothyroidism in ECD has not been thoroughly investigated. Methods: A prospective cohort study of biopsy-confirmed cases of ECD was conducted at the National Institutes of Health. Clinical, radiographic, and biochemical characteristics were assessed. All subjects underwent baseline evaluation with a thyroid function test, including TSH, free thyroxine (fT4) and total thyroxine (T4).Results: Sixty-one subjects with ECD (46 males, 54.3 ± 10.8 years) were evaluated. Sixteen subjects (26%) hadprimary hypothyroidism and were receiving thyroid hormone supplementation before enrollment, with a mean TSH 2.00 ±1.63 mcIU/mL (normal 0.27-4.20 mcIU/mL), fT4 1.52 ±1.51 ng/dL (normal 0.9-1.7 ng/dL), and T4 7.42 ±2.15 mcg/dL (normal 4.5-11.7 mcg/dL). The prevalence of primary hypothyroidism was higher than general population estimates (26% vs. 3.7%, P<0.05). No subject presented with myxedema coma or thyrotoxicosis. One subject (1.6%), a 61-year-old Caucasian female with ECD-related cerebellar dysfunction, retroperitoneal fibrosis, and osteosclerosis, harbored the BRAF V600E pathogenic variant and had a biochemical pattern suggestive of isolated central hypothyroidism: TSH 0.16 mcIU/mL, fT4 1.2 ng/dL and a normal baseline pituitary function test. She did not report symptoms suggestive of clinical thyroid disease and her physical examination was unremarkable. Pituitary MRI showed a small hypoenhancing lesion in the posterior aspect of the pituitary gland that is clinically insignificant. Dynamic TSH-secretion testing with a thyrotropin releasing hormone (200 μg IV synthetic TRH with serial TSH testing) demonstrated a blunted response in keeping with central hypothyroidism; baseline TSH 0.35 mcIU/mL, peak 2.90 mcIU/mL (ΔTSH <7 mcIU/mL). Conclusion: The prevalence of hypothyroidism (1 in 4) is high in subjects with ECD. Clinicians should have a low threshold to screen for hypothyroidism in this at-risk population. Central hypothyroidism is a rare manifestation of ECD and should be suspected in the setting of pituitary disease with a fT4 level below the laboratory reference range or low-normal levels in conjunction with a low, normal, or mildly elevated TSH.