Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients

Eur J Endocrinol. 2010 Aug;163(2):279-84. doi: 10.1530/EJE-10-0285. Epub 2010 May 11.


Aim: To evaluate, by using skin biopsy technique, the intraepidermal nerve fiber (IENF) density in a group of untreated patients with hypothyroidism, either overt (OH) or subclinical (SH), who did not complain of neurologic symptoms.

Methods: We evaluated 18 neurologically asymptomatic patients newly diagnosed with OH or SH. Fifteen healthy, age-matched, controls were also studied. A nerve conduction study was performed. Skin biopsy was carried out from the skin of upper thigh and distal leg. Nerve fiber density was measured using an immunofluorescence technique. The density of innervation was calculated by counting only fibers crossing the basement membrane.

Results: Electroneurographic parameters were similar in patients and controls. When compared with healthy controls, patients with OH or SH showed a significantly lower IENF density. As assessed by the proximal/distal fiber density ratio, the hypothyroid neuropathy was length dependent. When individually considered, an abnormally reduced IENF was observed in 60% of patients with OH at the distal leg and in 20% at the proximal site. In patients with SH, an abnormal IENF density was found at the distal leg in 25% of cases and at the proximal thigh in 12.5% of cases.

Conclusions: Our study provides the first direct demonstration of reduced IENF density in patients with OH or SH. In all patients, the IENF density reduction was length dependent. These findings suggest that a considerable number of untreated hypothyroid patients may have preclinical asymptomatic small-fiber sensory neuropathy.

MeSH terms

  • Adult
  • Aged
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Hypothyroidism / blood
  • Hypothyroidism / pathology*
  • Hypothyroidism / physiopathology
  • Male
  • Middle Aged
  • Nerve Fibers / pathology*
  • Neural Conduction
  • Peripheral Nervous System Diseases / blood
  • Peripheral Nervous System Diseases / pathology*
  • Peripheral Nervous System Diseases / physiopathology
  • Severity of Illness Index
  • Skin / innervation*
  • Skin / pathology
  • Statistics, Nonparametric
  • Thyrotropin / blood
  • Thyroxine / blood


  • Thyrotropin
  • Thyroxine