The LDIFLARE and CCM Methods Demonstrate Early Nerve Fiber Abnormalities in Untreated Hypothyroidism: A Prospective Study

Context: Recent studies using skin biopsy suggest presence of small-fiber neuropathy in subclinical hypothyroidism. This study uses two noninvasive methods-the laser Doppler imager flare technique (LDIFLARE) and corneal confocal microscopy (CCM)-to assess small-fiber function (SFF) and small-fiber structure (SFS), respectively, in newly diagnosed hypothyroidism (HT) before and after adequate treatment. Design and Setting: Single-center, prospective, intervention-based cohort study. Patients and Participants: Twenty patients with newly diagnosed HT (15 with primary HT and 5 with post-radioiodine HT) along with 20 age-matched healthy controls (HCs). Interventions: Patients with HT and HCs were assessed neurologically at diagnosis and baseline, respectively. The HT group was reassessed after optimal replacement (defined as TSH level of 0.27 to 4.20 mIU/L) with levothyroxine (LT4) and HCs were reviewed after 1 year. Main Outcome Measures: Neurologic assessment for small fibers was performed by using LDIFLARE for SFF and CCM for SFS; large fibers were studied by sural nerve conduction velocity (SNCV) and sural nerve amplitude (SNAP). Results: At baseline, both LDIFLARE (mean ± SD) (6.74 ± 1.20 vs 8.90 ± 1.75 cm2; P = 0.0002) and CCM nerve fiber density (CNFD) (expressed as number of fibers per mm2: 50.77 ± 6.54 vs 58.32 ± 6.54; P = 0.002) were significantly reduced in the HT group compared with HCs whereas neither SNCV nor SNAP was different (P ≥ 0.05). After optimal LT4 treatment, both LDIFLARE (7.72 ± 1.12 vs 6.74 ± 1.20 cm2; P ≤ 0.0001) and CNFD (54.43 ± 5.70 vs 50.77 ± 6.54 no./mm2; P = 0.02) improved significantly but remained significantly reduced compared to HCs (P = 0.008 and P = 0.01, respectively) despite normalization of TSH. Conclusions: This study demonstrates that dysfunction of small fibers precedes large neural fiber abnormalities in early HT. This can be reversed by replacement therapy to achieve a biochemically euthyroid state, but small-fiber neural outcomes continued to remain low compared with values in HCs.