Porphyrias are a heterogeneous group of heme biosynthesis disorders. Depending on the clinical picture and pathophysiology, they may be classified as acute vs chronic (nonacute), hepatic, erythropoietic, hepato-erythropoietic, cutaneous, neurovisceral, or porphyrias with cutaneous and neurovisceral symptoms. Acute intermittent porphyria (AIP) is the most common hepatic porphyria in Poland. In Europe, it is estimated to occur in 1–2 per 10 000 individuals; however, 80%–90% persons with pathogenic mutations remain asymptomatic. According to a register performed in the Institute of Hematology and Transfusion Medicine in Warsaw, the prevalence of AIP in Poland was 4.8 per 100 000 inhabitants.1 The symptoms occur more often in women than men, in a ratio of approximately 4:1. They usually appear in the third or fourth decade of life. AIP exacerbations rarely affect children and the elderly. The etiological factors of AIP are mutations in the gene encoding hydroxymethylbilane synthase, also called porphobilinogen deaminase.
Clinical course of AIP varies greatly. A vast majority of individuals with pathogenic mutations do not show any symptoms associated with porphyria throughout their lifetime. On the other hand, 3%–8% of patients experience recurrent exacerbations requiring numerous hospitalizations.2 Symptoms of AIP include abdominal pain, nausea, vomiting, peripheral nerve paresis or paralysis, coma, and / or mental disorders. They may be induced by many factors, such as drug or alcohol use, starvation, or stress. On physical examination, tachycardia and increased blood pressure may be observed. Due to a nonspecific clinical picture, AIP is often diagnosed too late, which poses a threat to patients’ lives. Additionally, numerous medications are contraindicated in AIP, because they may worsen the clinical condition.
In the first half of the 20th century, the mortality rate of AIP exacerbations was 50%–90%. If the nervous system was affected, 80% of patients died within 5 years.3 The main cause of death was paralysis of the respiratory muscles, but fatal cases due to pneumonia, sepsis, liver cirrhosis, sudden cardiac arrest, and deaths of unknown mechanism have also been reported.4,5 Currently, AIP exacerbations rarely result in death. However, if diagnosis is delayed or treatment with hemin-containing products is unavailable, mortality may reach 5%–20%.6 Typically, patients do not present any symptoms during remission, although paresis sometimes persists for months or years, or may even be permanent. The risk of hepatocellular carcinoma in patients with AIP is significantly greater than in the general population.7
Cardiovascular complications of hepatic porphyrias reported in the literature include myocardial infarction, cardiomyopathy, and Takotsubo syndrome.8-10 Foci of myocardial fibrosis were detected on autopsy.11 Two studies involving small patient groups showed decreased left ventricular ejection fraction and a higher incidence of atrial fibrillation in individuals with AIP, as compared with the control groups.12,13 The prevalence of hypertension is estimated at 30%–75% of cases, depending on the population, phase of the disease, and adopted definition.14,15
The pathomechanism of possible changes in the cardiovascular system remains unclear. The influence of toxic effect of δ-aminolevulinic acid (ALA), catecholamines, heme deficiency, or damage to the autonomic nervous system were postulated. The scientific data published so far do not allow for a clear determination of the impact of heme precursors on the heart.
The Acute Intermittent Porphyria Related Abnormalities in Cardiovascular System (AIPRACUS) study (ClinicalTrials.gov ID, NCT05882136) is a prospective, case-control study enrolling a cohort of patients examined during AIP exacerbations. Its major aim is to assess the impact of AIP on the cardiovascular system, with special focus on structural and functional changes in the heart and the incidence of selected cardiovascular risk factors in patients with AIP. Data on the blood pressure profile and cardiac arrhythmias will also be obtained. The relationship between urinary concentrations of heme precursors, ALA and porphobilinogen, and abnormalities of the circulatory system will be evaluated. Recruitment started in 2019, and the study is being performed at the National Institute of Cardiology and Institute of Hematology and Transfusion Medicine in Warsaw, Poland. The results will expand the current knowledge about the cardiovascular system in patients with AIP. In particular, they should answer the question whether porphyria may be a cause of impaired cardiac function and increased concentrations of myocardial injury or heart failure biomarkers. Spreading knowledge about porphyrias may contribute to improving patient prognosis.
Krzysztof Jaworski, MD, PhD, National Institute of Cardiology, ul. Alpejska 42, 04-628 Warszawa, Poland, phone: +48 22 343 42 59, email: kjaworski@ikard.pl
April 30, 2024.
May 7, 2024.
August 8, 2024.
None.
None.
None declared.
Jaworski K, Wasilewski R, Windyga J, et al. Cardiovascular abnormalities in patients with acute intermittent porphyria: the AIPRACUS study. Pol Arch Intern Med. 2024; 134: 16820. doi:10.20452/pamw.16820
- 1.
- Szlendak U, Lipniacka A, Bianketti J, et al. Porphobilinogen deaminase gene mutations in Polish patients with non-erythroid acute intermittent porphyria. Adv Clin Exp Med. 2015; 24: 63-68.Crossref
- 2.
- Gouya L, Ventura P, Balwani M, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020; 71: 1546-1558.Crossref
- 3.
- Slade C. Porphyria. Can Med Assoc J. 1949; 60: 392-395.Crossref
- 4.
- Bonkovsky HL. Neurovisceral porphyrias: what a hematologist needs to know. Hematology Am Soc Hematol Educ Program. 2005; 24-30.Crossref
- 5.
- Martin WJ, Heck FJ. The porphyrins and porphyria; a review of eighty-one cases. Am J Med. 1956; 20: 239-250.Crossref
- 6.
- Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015; 8: 201-214.Crossref
- 7.
- Baravelli CM, Sandberg S, Aarsand AK, et al. Acute hepatic porphyria and cancer risk: a nationwide cohort study. J Intern Med. 2017; 282: 229-240.Crossref
- 8.
- Eilenberg MD, Scobile BA. Prolonged neuropsychiatric disability and cardiomyopathy in acute intermittent porphyria. Br Med J. 1960; 1: 858-859.Crossref
- 9.
- Messas N, Willemain R, Bilger A, et al. Takotsubo syndrome triggered by acute intermittent porphyria attack: an unusual stressor for catecholamine-induced cardiomyopathy. Int J Cardiol. 2016; 207: 28-30.Crossref
- 10.
- Albright LF, Brown FJ. Acute myocardial infarction associated with acute porphyria. Am Heart J. 1954; 47: 108-111.Crossref
- 11.
- Macleod JG, Grant IWB. Intermittent acute porphyria. Edinb Med J. 1953; 60: 232-246.
- 12.
- Dhoble A, Patel MB, Abdelmoneim SS, et al. Relation of porphyria to atrial fibrillation. Am J Cardiol. 2009; 104: 373-376.Crossref
- 13.
- Panwar RB, Setia VV, Gupta BK, Saksena HC. Echocardiographic changes in cases of intermittent acute porphyria. Echocardiography. 1997; 14: 223-230.Crossref
- 14.
- Kostrzewska E, Zienkiewicz K, Nosal S, Stachurska H. Acute intermittent porphyria and arterial hypertension. Pol Arch Med Wewn. 1991; 86: 84-87.
- 15.
- Stewart MF. Review of hepatocellular cancer, hypertension and renal impairment as late complications of acute porphyria and recommendations for patient follow-up. J Clin Pathol. 2012; 65: 976-980.Crossref