Dyslipidemia is a metabolic hallmark of acute pain in sickle cell disease.

Individuals with sickle cell disease (SCD) experience intense acute episodic pain associated with vaso-occlusive events and persistent, often daily, chronic pain. Triggers for acute episodic pain include cold exposure, strenuous exercise, and hypoxia. The molecular mechanisms underlying acute pain in SCD are poorly defined. We asked whether acute pain was associated with an altered metabolomic profile in individuals with SCD. We performed untargeted metabolomics on plasma from 25 children with SCD obtained during two disease states: 1) during an acute pain episode, and 2) during baseline state of health ("baseline health"). Control plasma was analyzed from 25 race-matched healthy controls. We identified 318 dysregulated metabolites in SCD patients during baseline health relative to healthy controls. Baseline health SCD samples had elevated pyrimidine, polyamine, and methionine metabolites, whereas arginine and sphingomyelin metabolites were decreased. During acute pain, we identified 448 dysregulated metabolites relative to baseline health conditions in the same SCD patients. We found decreased amino acid metabolites and acyl-carnitines, consistent with hypoxia. Network analysis revealed eight metabolic modules that were significantly differentially correlated to healthy controls, baseline health, or SCD acute pain. Modules enriched for porphyrin metabolism were correlated with SCD during acute and baseline health conditions. Other modules identified prominent dyslipidemia during acute pain in SCD relative to baseline health and healthy controls. Furthermore, we identified a metabolic module characterized by multiple sphingomyelins that were reduced in SCD and correlated with acute pain. Our findings identify dyslipidemia and impaired oxidative metabolism as potential drivers of acute pain in SCD.