vitamin B12 deficiency and chronic cough and upper airway sensory neuropathy

PURPOSE: Vitamin B12 deficiency causes sensory neuropathy, that might contribute to the pathogenesis of chronic cough and pharyngo-laryngeal dysfunction. Increased nerve growth factor (NGF) levels have been demonstrated in cobalamin deficiency. We investigated upper and lower airway responsiveness and cough threshold to histamine before and after vitamin B12 supplementation (cobalamin 1000 mcg weekly for 2 months) in 40 patients with chronic unexplained cough, 25 with B12 deficiency (serum value below 300 pg/ml) and 15 controls with no nutritional lack. In a subgroup of subjects, NGF expression in pharyngeal mucosa was assessed. METHODS: Patients and controls underwent spirometry, measurement of exhaled nitric oxide (FeNO), and histamine inhalation challenge with assessment of extrathoracic airway (EA) threshold (PC25MIF50), bronchial threshold (PC20FEV1) and cough threshold (PC5coughs). Hyperresponsiveness (HR) was diagnosed for thresholds below 8 mg/ml. Six patients with vitamin B12 deficiency and 4 controls underwent oropharyngeal biopsy to evaluate the relationship between airway dysfunction and NGF expression. RESULTS: Patients with vitamin B12 deficiency had significantly lower EA and cough thresholds, but similar bronchial threshold than controls. FeNO was in the normal range in both groups. Pharyngeal biopsy examination showed that patients with vitamin B12 deficiency had significantly higher expression of NGF than cough patients without deficiency (NGF score 6.7 +/- 0.8 versus 2.8 +/- 0.4, p < 0.02). Vitamin B12 serum levels were inversely related to NGF score (r= 0.561, p < 0.02) (see the figure, where circles are patients with vitamin deficiency, triangles are controls). After vitamin B12 supplementation, histamine thresholds improved significantly but only in patients with vitamin deficiency: PC20FEV1 from 12.2 ± 4 to 18 ± 4 mg/ml (p < 0.01), PC25MIF50 from 3.5 ± 1 to 18.2 ± 4 mg/ml (p < 0.001) and PC5coughs from 2.3 ± 1 to 14.5 ± 4 mg/ml (p < 0.01); no significant change was observed in control subjects. CONCLUSION: In vitamin B12 deficiency the decreased modulation of neurotrophic agents may favour neurogenic inflammation, leading to chronic cough and airway dysfunction. CLINICAL IMPLICATIONS: Vitamin B12 deficiency should be investigated in subjects with unexplained cough.