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Impaired Acylcarnitine Profile in Transfusion-Dependent Beta-Thalassemia Major Patients in Bangladesh

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Impaired Acylcarnitine Profile in Transfusion-Dependent Beta-Thalassemia Major Patients in Bangladesh

Suprovath Kumar Sarker et al. J Adv Res.

Abstract

Patients with beta-thalassemia major (BTM) suffer from fatigue, poor physical fitness, muscle weakness, lethargy, and cardiac complications which are related to an energy crisis. Carnitine and acylcarnitine derivatives play important roles in fatty acid oxidation, and deregulation of carnitine and acylcarnitine metabolism may lead to an energy crisis. The present study aimed to investigate carnitine and acylcarnitine metabolites to gain an insight into the pathophysiology of BTM. Dried blood spots of 45 patients with BTM and 96 age-matched healthy controls were analyzed for free carnitine and 24 acylcarnitines by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Although medium chain acylcarnitine levels were similar in the patients with BTM and healthy controls, free carnitine, short chain acylcarnitines, long chain acylcarnitines, and total acylcarnitine levels were significantly lower in patients with BTM than in the healthy controls (P < 0.05). Moreover, an impaired fatty acid oxidation rate was observed in the patients with BTM, as manifested by decreased fatty acid oxidation indicator ratios, namely C2/C0 and (C2 + C3)/C0. Furthermore, an increase in the C0/(C16 + C18) ratio indicated reduced carnitine palmitoyltransferase-1 (CPT-1) activity in the patients with BTM compared with that in the healthy controls. Thus, a low level of free carnitine and acylcarnitines together with impaired CPT-1 activity contribute to energy crisis-related complications in the patients with BTM.

Keywords: Beta-thalassemia major; Carnitine Palmitoyltransferase-1 activity; Carnitine-acylcarnitine levels; Impairment in fatty acid oxidation.

Figures

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Fig. 1
Fig. 1
Free and total carnitine levels in the BTM patients and control participants. The dried blood spot (DBS) specimens were analyzed using LC-MS/MS to determine free carnitine and total carnitine levels. The DBS results reflect levels of analytes in the blood of BTM patients (n = 45) and healthy controls (n = 96). (A) Free carnitine levels in the BTM patients (31.59 ± 7.39 nmol/mL) and healthy participants (42.93 ± 8.683 nmol/mL), (B) Total carnitine levels in the BTM patients (42.64 ± 10.79 nmol/mL) and healthy participants (64.25 ± 11.76 nmol/mL). A P-value of <0.05 was considered statistically significant.
Fig. 2
Fig. 2
LC-MS/MS-based representative MRM chromatograms for short chain acylcarnitines for BTM patients and healthy controls. The X-axis represents time after run in minute and Y-axis represent metabolites counted per second. The upper-left number inside the MRM chromatogram represents precursor ion followed by >sign and then the upper right number represents the target ion. Each metabolite detected has been shown vertically above the peak with a capital C followed by digit(s). The concentration of each short chain (SC) acylcarnitine is proportional to the peak area. The upper panel and lower middle panel indicate controls, whereas the upper middle panel and the bottom panel indicate patients.
Fig. 3
Fig. 3
LC-MS/MS-based representative MRM chromatograms for medium chain acylcarnitines for BTM patient and healthy control. The X-axis represents time after run in minute and Y-axis represent metabolites counted per second. The upper-left number inside the MRM chromatogram represents precursor ion followed by >sign and then the upper right number represents the target ion. Each metabolite detected has been shown vertically above the peak with a capital C followed by digit(s). The concentration of each medium chain (MC) acylcarnitine is proportional to the peak area. The upper panel and lower middle panel indicate controls, whereas the upper middle panel and the bottom panel indicate patients.
Fig. 4
Fig. 4
LC-MS/MS-based representative MRM chromatograms for long chain acylcarnitines for BTM patient and healthy control. The X-axis represents time after run in minute and Y-axis represent metabolites counted per second. The upper-left number inside the MRM chromatogram represents precursor ion followed by >sign and then the upper right number represents the target ion. Each metabolite detected has been shown vertically above the peak with a capital C followed by digit(s). The concentration of each long chain (LC) acylcarnitine is proportional to the peak area. The upper panel and lower middle panel indicate controls, whereas the upper middle panel and the bottom panel indicate patients.
Fig. 5
Fig. 5
LC-MS/MS generated representative multiple reaction monitoring (MRM) chromatograms for internal standards. The X-axis represents time after run in minute and Y-axis represent metabolites counted per second. The upper-left number inside the MRM chromatogram represents precursor ion followed by >sign and then the upper right number represents the target ion. Each metabolite detected has been shown vertically above the peak with a capital C followed by digit(s) and then IS for internal standard. The concentration of each metabolite is proportional to the peak area. The internal standards are presented in the chromatogram as (a) 2H9-free carnitine (C0 IS), (b) 2H3-acetylcarnitine (C2 IS), (c) 2H3-propionylcarnitine (C3 IS), (d) 2H3-butyrylcarnitine (C4 IS), (e) 2H9-Isovalerylcarnitine (C5 IS), (f) 2H3-Glutarylcarnitine (C5DC IS), (g) 2H3-Hexanoylcarnitine (C6 IS), (h) 2H3-Octanoylcarnitine (C8 IS), (i) 2H3-Decanoylcarnitine (C10 IS), (j) 2H3-Lauroylcarnitine (C12 IS), (k) 2H9-Myristoylcarnitine (C14 IS), (l) 2H3-Palmitoylcarnitine (C16 IS), and (m) 2H3-Stearoylcarnitin (C18 IS).

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