Therapeutic strategies for acute intermittent porphyria

Abstract

acute intermittent porphyria, heme, carbohydrate loading, givosiran (siRNA), mRNA therapy Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by mutations in porphobilinogen deaminase (PBGD), the third enzyme of the heme synthesis pathway. Symptoms of AIP usually manifest as intermittent acute attacks with occasional neuropsychiatric crises. The management of AIP includes treatment of acute attacks, prevention of attacks, long-term monitoring and treatment of chronic complications. Intravenous injection of heme is the most effective method of treating acute attacks. Carbohydrate loading is used when heme is unavailable or in the event of mild attacks. Symptomatic treatment is also needed during attacks. Prevention of attacks includes eliminating precipitating factors, heme prophylaxis and liver transplantation. New treatment options include givosiran (siRNA) to down-regulate ALA synthase-1 (ALAS1) and the messenger RNA of PBGD (PBGD mRNA) delivered to the liver cells of patients with AIP. Long-term monitoring of chronic complications includes regular liver-kidney function and hepatocellular carcinoma (HCC) screening.

Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations

“…Clinical management of AHP is complex and is based on an individual-based approach and has been widely discussed in previous literature ( Balwani et al, 2017 ; Anderson, 2019 ; Fontanellas et al, 2019 ; Zhao et al, 2020 ; Bustad et al, 2021 ; Souza et al, 2021 ; Figure 5 ). Most therapeutic measures currently used in the treatment of patients with AHP have been developed based on the expanding knowledge of heme biosynthesis group inhibitor or activator triggers, as well as in new regulators of metabolites or transcription factors involved with different enzyme steps ( Balwani et al, 2017 ; Anderson, 2019 ; Fontanellas et al, 2019 ; Zhao et al, 2020 ; Bustad et al, 2021 ). There are three different periods and approaches during the treatment of AHP for the proper management of acute and chronic complications of the disease ( Anderson and Collins, 2006 ; Anderson, 2019 ).…”

“…Heme arginate (Normosang ® ) can be used during attacks with a dose of 3 mg/kg per day (up to 250 mg per day) for 4 days. Both presentations need careful clinical and laboratorial monitoring during infusion periods, and different chronic and acute adverse events have been correlated with them ( Anderson and Collins, 2006 ; Balwani et al, 2017 ; Anderson, 2019 ; Fontanellas et al, 2019 ; Zhao et al, 2020 ; Bustad et al, 2021 ; Souza et al, 2021 ).…”

Use of intrathecal drug infusion pump with combined morphine and bupivacaine medication for the treatment of abdominal pain due to Acute Intermittent Porphyria (AIP)

“…It is an uncommon genetic disease of autosomal dominant inheritance caused by hydroxymethylbilane synthase (HMBS) deficiency.In patients with AIP, there is an increase in the regulation of ALA synthase-1 (ALAS1), the liver's first heme synthesis pathway, resulting in increased production and accumulation of delta-aminolevulinic acid and porphobilinogen in organs and tissues. of the human body [17] and may cause gastrointestinal, neurological, psychological, endocrine and urological symptoms [16]. It is estimated that the incidence of AIP cases in Europe is approximately 1/20.000 individuals [11], while the prevalence of symptomatic cases of AIP in most countries is only 5.4 per million per year [12].…”

Mechanistic modelling of enzyme‐restoration effects of new recombinant liver‐targeted proteins in acute intermittent porphyria

“…However, hemin requires hospitalization has it has to be given intravenously. Patients with chronic acute attacks develop side effects as a consequence of frequent hemin administrations such as central vein damage and iron overload, which can lead to chronic inflammatory response (Schmitt et al, 2018) and hepatic damage (Zhao et al, 2020). Indeed, hemin administration induces the activity of the key enzyme of heme catabolism, the heme oxygenase, resulting in the reduction of the regulatory heme concentration in the cell.…”