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Hyperhomocysteinemia in patients with acute porphyrias: A potentially dangerous metabolic crossroad?

      Highlights

      • In AP, 5-aminolevulinate-synthase(ALAS1) induction,a vit.B6-dependent enzyme,is present
      • Vit.-B6 is requested by enzymes that catabolize homocysteine(Hcy).
      • Heme itself is an important cofactor for CBS.
      • AP patients show frequently HHcy that may result from vitamin and heme deficiency.
      • HHcy may represent an indirect marker of ALAS1-induction

      Abstract

      Background

      Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic 5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly, both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate, PLP) an important cofactor of ALAS1 and of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Moreover, heme itself is an important cofactor for CBS.

      Aim

      to assess plasma Hcy status and HHcy main determinants in patients with AP.

      Materials and methods

      A total of 46 patients with AP (31 with Acute Intermittent Porphyria,15 with Variegate Porphyria) were assessed for clinical status (symptomatic vs. asymptomatic), serum Hcy, Cysteine (Cys), Vit.B6, Vit.B12, red blood cell folates and urinary delta-aminolevulinic acid (ALA) and porphobilinogen(PBG) levels (mean of six measurements).

      Results

      Symptomatic AP patients had significantly higher urinary ALA and PBG levels, plasma Hcy, HHcy prevalence and Hcy/Cys ratio when compared to asymptomatic carriers of AP. Even though no significant correlation was observed between ALA/PBG urinary levels and serum Hcy levels, patients with higher levels of ALA and PBG had significantly higher levels of Hcy, a higher prevalence of moderate-to severe HHcy and serum PLP levels below the 25th percentile of a reference assessment with 300 healthy Italian subjects(<45nmol/L).

      Conclusions

      Most patients with symptomatic AP present HHcy resulting from alterations in sulphur amino acid metabolism. HHcy may represent an indirect marker of ALAS1 induction and its prevalence may be suggestive of a role of HHcy in the pathogenesis and/or comorbidities of AP.

      Keywords

      Abbreviations:

      AIP (Acute Intermittent porphyria), ALA (delta aminolevulinic acid), ALAS1 (5-aminolevulinate synthase 1), AP (Acute Porphyrias), APA (Acute Porphyric Attack), CBS (Cystathionine beta-Synthase), CGL (cystathionine γ-lyase), Cys (Cysteine), Hcy (Homocysteine), HHcy (Hyperhomocysteinemia), MTHFR (Methylene-Tetrahydrofolate Reductase), PBG (Porphobilinogen), PLP (Pyridoxal-phosphate), VP (Variegate Porphyria)
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