Profiling of Serum Metabolites of Acute Intermittent Porphyria and Asymptomatic HMBS Mutation Carriers

Abstract

This study aims to present the serum metabolite profiles of patients with acute intermittent porphyria (AIP) and identify specific metabolites that could potentially discriminate between AIP, asymptomatic HMBS mutation carriers, and healthy individuals. The study cohort included 46 female participants: 21 AIP patients, 5 asymptomatic carriers, and 20 ‘normal’ participants (without HMBS gene mutation). Serum samples were analyzed for 157 selected metabolites or clinical variables using an assay combining liquid chromatography MS/MS and direct flow injection. AUC analysis was used to distinguish unique variables between the three groups. A total of 15 variables differed significantly between the AIP and normal control group (VIP score > 1.0 and p < 0.05 with FDR correction). In AIP patients, the levels tyrosine, valine, and eGFR were significantly lower, and the levels of sphingomyelin C16:0, C24:0, C24:1, phosphatidylcholine diacyl C32:1, C36:1, C36:3, ornithine, sarcosine, citrulline, blood urea nitrogen AST, and ALT were significantly higher. The AUC of these 15 variables in discriminating between normal and AIP patients ranged between 0.73 and 0.94 (p < 0.05). In conclusion, serum metabolic profiles differ between normal individuals and patients carrying the HMBS mutation. The unique metabolites associated with AIP identified in this study may be useful for monitoring the development of AIP symptoms.

Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

“…Most recently, it emerged that AIP experimental models show impaired glucose metabolism and mitochondrial respiration capacity during acute attacks, while carriers of AIP displayed high body weight, hyperinsulinemia, and alterations in serum lipid profiles combined with IR [16,38,39]. These findings suggest that AIP may be considered a genetic disorder characterized by an umbrella of metabolic dysfunctions, thereby adding new additional knowledge about its pathophysiology and, possibly, novel curative strategies.…”

“…Several studies underlined that caloric impoverishment exasperates acute attacks of AIP and many individuals with AIP with severe symptomatology maintain an inadequate carbohydrate intake, suggesting that dietary carbohydrates or glucose infusions may be supplemented to reduce the severity of these events [38][39][40][41][42]. Matkovic and colleagues demonstrated that the hormonal regulation of carbohydrates may be modeled by porphyrinogenic drugs such as 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).…”

“…In another study, the serum metabolic profiles of patients with AIP denoted 15 variables which could discriminate between asymptomatic patients with AIP and healthy subjects. Among them, serum analysis by liquid chromatography revealed that levels of several lipid species, including sphingomyelins (C16:0, C24:0, and C24:1) and phosphatidylcholines (C32:1, C36:1, and C36:3), were significantly higher in the serum of patients with AIP [39]. Conversely, branched-chain amino acids (BCAA: valine, leucine, isoleucine) and aromatic amino acids (AAA: tryptophan, tyrosine) were significantly lower in patients with AIP.…”

Acute intermittent porphyria: prevalence of pathogenic HMBS variants in China, and epidemiological survey in Hebei Province, China

“…Alcohol, smoking, drugs, fasting/hunger, and changes in women's sex hormone levels are the common precipitants (1,9). Differences have been found in the serum metabolic profiles between normal individuals and patients carrying the HMBS variant (10). All individuals with pathogenic HMBS gene variants are at risk of developing acute attacks, and chronic complications such as hepatocellular carcinoma, hypertension, and chronic renal failure can occur in both symptomatic AIP and latent patients with pathogenic HMBS variants (8,11).…”

Evaluation of Metabolic Changes in Acute Intermittent Porphyria Patients by Targeted Metabolomics

“…The evaluation of the genome in combination with the metabolome alterations produced by AIP might shed light on these mechanisms [ 9 , 10 , 11 ]. Several metabolic alterations produced by AIP have been previously reported [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. For instance, steroids are incriminated in the induction of porphyria [ 19 ] and our group reported that AIP alterations in the urinary steroidome are correlated with ALA concentration [ 15 , 16 ].…”