Low vitamin B12 levels and gastric parietal cell antibodies in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders

Abstract

In up to 80 % of patients, neuromyelitis optica (NMO, Devic’s syndrome), is associated with antibodies to aquaporin-4 (AQP4-Ab), the most abundant water channel in the central nervous system [2, 6–8, 10, 11]. However, AQP4 is also highly expressed in the basal cell membrane of gastric parietal cells (GPC) and, accordingly, serum AQP4-Ab from patients with NMO has been shown to bind to GPC [10]. The latter fact is of particular interest because humoral autoimmunity to GPC is a common cause of vitamin B12 deficiency and because low vitamin B12 levels can cause subacute combined degeneration of the spinal cord (SACD) as well as optic neuropathy and may thus aggravate neurological deficits in patients with NMO, a disease mainly characterized by spinal cord and optic nerve damage (Fig. 1) [14]. Moreover, AQP4-Ab is known to be frequently associated with other, co-existing autoantibodies; however, the frequency of gastric parietal cell antibodies (PCA) in NMO has not been systematically studied so far. We retrospectively identified 13 patients with NMO spectrum disorders (NMOSD) in whom vitamin B12 levels had been determined as part of the diagnostic workup (Table 1). All of these patients were AQP4-IgGpositive. In 6 of the 13 patients (46.2 %) vitamin B12 serum levels were low (\300 pmol/l) [12]. Levels ranged between 118 and 204 pmol/l (median, 150 pmol/l) (Table 1). Methylmalonic acid (MMA) and homocystein (HC), respectively, two markers of vitamin B12 deficiency, had been determined in two of these patients and were elevated in both (MMA: 5.19 mg/g creatinine, reference range,\2; HC: 15.4, reference range,\13.9). In three further patients, repeat testing was done and confirmed the low serum vitamin B12 status (160 pmol/l at baseline and 170 pmol/l 24 months later in patient 1; 204 at baseline and 259 64 months later in patient 2; 166 at baseline, 174 1 month later, and 139 another 18 months later in patient 3). Classical cytoplasmic PCA were present in three patients, two of whom had low vitamin B12 levels. Of these three patients, two had anti-H/K-ATPase (HKA) and none had anti-intrinsic-factor antibodies (IFA); one had classic PCA but was negative for both HKA and IFA. The remaining four patients with low vitamin B12 levels were all negative for HKA and IFA. Of note, vitamin B12 levels were also not very high in most of the remaining patients (median, 365 pmol/l; after excluding one patient with values[1500, which indicate possible vitamin B12 supplementation). Disease duration at the time of blood sampling did not differ significantly between patients with vitamin B12 levels \300 pmol/l and the remaining patients (68 vs. 42 months). Our results suggest that low vitamin B12 serum levels may be relatively common in AQP4-Abpositive NMOSD. The finding that a subgroup of patients harbors HKA is in line with a known predisposition towards humoral autoimmunity in patients with AQP4-Abpositive NMO, which has been previously reported in association with myasthenia gravis [5, 9], connective tissue disorders [4, 13, 15], or celiac disease [1, 3]. Interestingly, S. Jarius (&) B. Wildemann Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany e-mail: sven.jarius@med.uni-heidelberg.de