A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy

About half of patients with Graves’ disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves’ ophthalmopathy.

Infant urinary metabolomic profile in a fatal acute methadone intoxication

A case report suspicious for a Sudden Infant Death Syndrome is here described. Pathological findings were consistent with an acute respiratory failure while toxicological analysis revealed an elevated blood methadone concentration. Death was then ascribed to an acute methadone intoxication. In addition to the routinary approach, the urinary sample collected at autopsy was investigated with a 1H NMR metabolomic approach and the identified metabolomic profile was challenged with the urinary metabolomic profiles previously obtained from 10 newborns who experienced perinatal asphyxia and 16 healthy control newborns. Intriguingly, the urinary profile of the methadone intoxicated infant was very similar to those belonging to the perinatal asphyxia newborns, especially to those belonging to the newborns characterised by the worst outcome. The results offer several hints on a shared metabolic derangement between different mechanisms of asphyxia/hypoxia. To the best of the authors’ knowledge, this is the first report of the use of a metabolomic approach in a pathological case, in which metabolomics offers useful additional information regarding the mechanism and the cause of death.

Metabolomic Profile Differences Between Demented and Non-Demented APOE4 Carriers in the Long Life Family Study

The apolipoprotein ε4 (APOE4) is the most prevalent genetic risk factor for late-onset Alzheimer’s Disease (AD). Here we assessed the metabolomic profile differences between APOE4 carriers who develop AD vs. who do not in a sample of 142 participants, aged 65-99 years in the Long Life Family Study (LLFS). Of 7,321 metabolites, we applied a generalized estimating equation model and identified 137 metabolites significantly associated with AD. Subsequent multivariate analyses were performed for prediction and clustering recognition. Among annotated metabolites, 8 metabolites in the eicosanoids and docosanoids group, 3 metabolites in the fatty acids group, and arabitol were associated with elevated risks of AD (OR: 1.6-2.3). On the other hand, a different set of metabolites were associated with reduced risks of AD (OR: 0.34-0.64). These metabolomic profile differences can be used to help with early diagnosis in the population of older APOE4 carriers in the pre-clinical stage.