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Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long\u2010term data for tHcy and related parameters for an AIP patient cohort (n\u00a0=\u00a037) in different clinical disease\u2010states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy &gt;\u200915\u2009\u03bcmol\/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\u00a0\u03bcmol\/L; range: 10\u2010129 vs median tHcy: 14.5\u00a0\u03bcmol\/L; range 6\u201077). Long\u2010term serial analyses showed a high within\u2010person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%\u201078.8%). HHcy was frequently associated with low blood concentrations of pyridoxal\u20105\u2032\u2010phosphate and folate, while cobalamin concentration and the allele distribution of the methylene\u2010tetrahydrofolate\u2010reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small\u2010interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105\u2009\u03bcmol\/L; range 16\u2010212). Screening of amino acids in plasma by liquid\u2010chromatography showed co\u2010increased levels of methionine (median 71\u2009\u03bcmol\/L; range 23\u2010616; normal &lt;40), suggestive of acquired deficiency of cystathionine\u2010\u03b2\u2010synthase. The kynunerine\/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme\u2010dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co\u2010increase of tHcy and methionine resembling classic homocystinuria.<\/jats:p>","DOI":"10.1002\/jimd.12391","type":"journal-article","created":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T00:54:19Z","timestamp":1618620859000},"page":"961-971","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2644-1213","authenticated-orcid":false,"given":"Jordi","family":"To\u2010Figueras","sequence":"first","affiliation":[{"name":"Biochemistry and Molecular Genetics Department Hospital Cl\u00ednic de Barcelona, Institut d'Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"Wijngaard","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department Hospital Cl\u00ednic de Barcelona, Institut d'Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Garc\u00eda\u2010Villoria","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department Hospital Cl\u00ednic de Barcelona, Institut d'Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aasne K.","family":"Aarsand","sequence":"additional","affiliation":[{"name":"Norwegian Porphyria Centre (NAPOS), Department of Medical Biochemistry and Pharmacology Haukeland University Hospital  Bergen Norway"},{"name":"Norwegian Organization for Quality Improvement of Laboratory Examinations Haraldsplass Deaconess Hospital  Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Dermatology Department Hospital Cl\u00ednic de Barcelona, Institut d'Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramon","family":"Deulofeu","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department Hospital Cl\u00ednic de Barcelona, Institut d'Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merc\u00e8","family":"Brunet","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department Hospital Cl\u00ednic de Barcelona, Institut d'Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c0lex","family":"G\u00f3mez\u2010G\u00f3mez","sequence":"additional","affiliation":[{"name":"Integrative Pharmacology and Systems Neuroscience Group Institut Municipal Investigaci\u00f3 M\u00e8dica (IMIM), Hospital del Mar  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oscar J.","family":"Pozo","sequence":"additional","affiliation":[{"name":"Integrative Pharmacology and Systems Neuroscience Group Institut Municipal Investigaci\u00f3 M\u00e8dica (IMIM), Hospital del Mar  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sverre","family":"Sandberg","sequence":"additional","affiliation":[{"name":"Norwegian Porphyria Centre (NAPOS), Department of Medical Biochemistry and Pharmacology Haukeland University Hospital  Bergen 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