Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran

Abstract

Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients.In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10-129 vs median tHcy: 14.5 μmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5 0 -phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolatereductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 μmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-β-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a coincrease of tHcy and methionine resembling classic homocystinuria.

Multiple roles of haem in cystathionine β-synthase activity: implications for hemin and other therapies of acute hepatic porphyria

“…This latter explanation is strongly supported by their observation of a prompt decline in plasma [Hcy] upon haem arginate administration that gave way shortly (3 days) after termination of haem therapy to a return of the elevation induced by givosiran. The study by To-Figueras et al [130] confirmed the fluctuating moderate elevation of plasma [Hcy] in AIP patients under basal conditions and the greater elevation induced by givosiran therapy, with levels of up to 212 µM having been observed. The latter authors also reported that patients with recurrent attacks requiring haem therapy presented with raised Hcy levels over a long period of observation spanning several years.…”

“…With gene therapies, the Hcy elevation is more likely to occur if inhibition of haem biosynthesis is the primary target. This has now been borne out by the recently reported [129,130] Hcy elevation by givosiran.…”

“…The elevation of plasma [Met] observed in both studies [129,130] suggests impaired conversion of Hcy to Met, possibly mediated by the MTHFR polymorphism and/or decreased availability of hepatic folate and B 12 .…”

“…Both the French and Italian Porphyria Centres and others in the Envision givosiran trial have observed strong elevations of [Hcy] in porphyric patients (see [129] and references cited therein). Notable among these reports are those by Petrides et al [129] and To-Figueras et al [130]. In [129], 2 AIP patients receiving 5-ALAS 1 gene silencing therapy with givosiran developed strong elevations of plasma [Hcy] of 100-200 and 100-400 µM.…”

“…The TDO status may also be subject to a dual effect of haem: initial activation by an increase, followed by subsequent inhibition by a decrease, in haem availability. The plasma [Kyn]/[Trp] ratio, a measure of TDO or IDO activity, was reported [130] for 9 AIP patients undergoing givosiran therapy over a 6-16-month period, and found to be unaltered. Whereas no definite conclusions could be made of the observed parameters of this ratio, compared to control values in the literature (see, e.g.…”