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

Ventura, Paolo; Corradini, Elena; Pierro, Elena Di; Marchini, Stefano; Marcacci, M; Cuoghi, Chiara; Buzzetti, Elena; Pietrangelo, Antonello

doi:10.1016/j.ejim.2020.04.002

Cited by 24 publications

(27 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The studies were recently extended by Ventura and coworkers [ 14 ]. They investigated 46 acute porphyria (AP) patients which they divided in three groups: symptomatic patients (AP-SP), patients with biochemical alterations (AP-BA), and asymptomatic carriers (AP-AC).…”

Section: Discussionmentioning

confidence: 99%

“…Since two groups [ 13 , 14 ] had reported that plasma homocysteine can be elevated in patients with acute porphyrias, we also measured plasma homocysteine levels by LC/MS/MS in our patients: unexpectedly, the first homocysteine level measured was 113 μmol/l in patient A (at the day of the severe drug reaction) and 408 μmol/l in patient B (after recovery from the pancreatitis). Homocysteine plasma levels were followed up and remained consistently high (increasing to 136 μmol/l in patient A), until they declined 3 months after discontinuation of givosiran.…”

Section: Plasma Homocysteine Measurements In Both Patientsmentioning

confidence: 98%

See 1 more Smart Citation

Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Petrides¹,

Klein

Schuhmann³

et al. 2021

Ann Hematol

View full text Add to dashboard Cite

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC–MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Plasma Homocysteine Measurements In Both Patientsmentioning

confidence: 98%

Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Petrides¹,

Klein

Schuhmann³

et al. 2021

Ann Hematol

View full text Add to dashboard Cite

show abstract

“…Two previous studies, one from the group of Dr To-Figueras, already reported high prevalence of elevated plasma total homocysteine (P-tHcy) levels (hyperhomocysteinemia, HHcy) in symptomatic AIP, which was more frequent in those patients receiving heme replacement therapy due to recurrent disease. 1,2 HHcy is not a benign condition, as it has been related with the development of cardiovascular and neurological damage. We read with interest a new study from the same group recently published in this Journal, 3 where these observations are substantiated and the potential mechanisms underlying HHcy are further addressed.…”

mentioning

confidence: 99%

Acute intermittent porphyria, givosiran, and homocysteine

Fontanellas

Ávila

Arranz

et al. 2021

J of Inher Metab Disea

View full text Add to dashboard Cite

“…In the 2 studies in AIP patients [1,2], plasma [Hcy] was elevated in ~ 60% of small samples of patients (n=24-46), with no observed changes in serum folate or B 12 , but with decreased levels of PLP. [Hcy] was higher in symptomatic and biochemically characterised (by raised urinary 5-ALA and PBG levels), compared with asymptomatic, patients and was more pronounced in patients receiving haem therapy [2], though the earlier study [1] reported lower [Hcy] after haem therapy.…”

Section: Homocysteine Metabolism and Changes In Acute Intermittent Porphyriamentioning

confidence: 99%

“…The present review discusses the role of haem in control of activity of cystathionine synthase (CBS: EC 4.2.1.22) and advances a hypothesis postulating that this control is exerted by the haem cofactor at multiple levels. This hypothesis was prompted by the reported [1,2] increase in the plasma concentration of the cardiovascular risk factor [3][4][5][6] homocysteine (Hcy) in patients with acute intermittent porphyria (AIP), which was attributed to inhibition of CBS activity by depletion of its other cofactor pyridoxal 5-phosphate (PLP). Further evidence has very recently emerged for a greater plasma Hcy elevation in some patients undergoing a specific gene therapy (see below).…”

Section: Introductionmentioning

confidence: 99%

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

Badawy

2021

Bioscience Reports

View full text Add to dashboard Cite

The role of haem in the activity of cystathionine b-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5¢-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase, and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase and subsequent utilisation of PLP by enhanced kynurenine aminotransferase and kynureninase activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed.

show abstract

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

Cited by 24 publications

References 55 publications

Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Acute intermittent porphyria, givosiran, and homocysteine

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

Contact Info

Product

Resources

About