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Background and Aims: Acute porphyria is a chronic recurrent disease with late diagnosis, heterogeneous clinical presentations and potentially devastating complications. The study aimed at providing real-world evidence on the natural course of acute porphyria, patient characteristics, disease burden, and healthcare utilization before diagnosis., Methods: This observational study used anonymized claims data covering 8 365 867 persons from German statutory health insurance, spanning 6 years (2015-2020). Patients with at least one diagnosis of acute porphyria during the index period (2019-2020) were classified into three groups by attack frequency. These findings were compared with two age- and sex-adjusted reference groups: the general population and fibromyalgia patients. Prevalence over the index period was calculated for all porphyria patients and those with active acute porphyria., Results: We revealed a prevalence of 79.8 per 1 000 000 for acute porphyria, with 12.9 per 1 000 000 being active cases. Acute porphyria patients, particularly with frequent attacks, demonstrated a higher comorbidity burden compared to the general population. Within the year before the recorded diagnosis, patients with acute porphyria required a median of 23.0 physician visits, significantly higher than the general population's 16.0. Additionally, 33.8% were hospitalized at least once during this period, a notably higher proportion than the general population (19.3%)., Conclusions: This study's findings, collected before the introduction of givosiran, as the first approved preventive therapy for acute porphyria in Europe, highlight the need for healthcare strategies and policies tailored to the complex needs of acute porphyria patients. The significant healthcare demands, heightened comorbidity burden, and increased healthcare system utilization emphasize the urgency of developing a comprehensive support infrastructure for these patients. Also, these acute porphyria real-world findings provide additional insights on disease characteristics in Germany., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex., Methods: All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers., Results: We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%., Conclusion: This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic 5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly, both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate, PLP) an important cofactor of ALAS1 and of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Moreover, heme itself is an important cofactor for CBS., Aim: to assess plasma Hcy status and HHcy main determinants in patients with AP., Materials and Methods: A total of 46 patients with AP (31 with Acute Intermittent Porphyria,15 with Variegate Porphyria) were assessed for clinical status (symptomatic vs. asymptomatic), serum Hcy, Cysteine (Cys), Vit.B6, Vit.B12, red blood cell folates and urinary delta-aminolevulinic acid (ALA) and porphobilinogen(PBG) levels (mean of six measurements)., Results: Symptomatic AP patients had significantly higher urinary ALA and PBG levels, plasma Hcy, HHcy prevalence and Hcy/Cys ratio when compared to asymptomatic carriers of AP. Even though no significant correlation was observed between ALA/PBG urinary levels and serum Hcy levels, patients with higher levels of ALA and PBG had significantly higher levels of Hcy, a higher prevalence of moderate-to severe HHcy and serum PLP levels below the 25 th percentile of a reference assessment with 300 healthy Italian subjects(<45nmol/L)., Conclusions: Most patients with symptomatic AP present HHcy resulting from alterations in sulphur amino acid metabolism. HHcy may represent an indirect marker of ALAS1 induction and its prevalence may be suggestive of a role of HHcy in the pathogenesis and/or comorbidities of AP., (Copyright © 2020. Published by Elsevier B.V.)

Porphyrias are rare genetic disorders which cause a deficiency in the enzymes involved in the biosynthesis of heme. The treatment of epilepsy in patients with acute intermittent porphyria can be difficult since many anticonvulsants can increase heme synthesis and trigger porphyric attacks. We report a patient with focal epilepsy successfully treated with eslicarbazepine without exacerbation of porphyria.

Purpose: Acute intermittent porphyria (AIP) is a rare inborn error of heme biosynthesis characterized by life-threatening acute attacks. Few studies have assessed quality of life (QoL) in AIP and those that have had small sample sizes and used tools that may not have captured important domains., Methods: Baseline data from the Porphyrias Consortium's Longitudinal Study were obtained for 259 patients, including detailed disease and medical history data, and the following Patient-Reported Outcomes Measurement Information System (PROMIS) scales: anxiety, depression, pain interference, fatigue, sleep disturbance, physical function, and satisfaction with social roles. Relationships between PROMIS scores and clinical and biochemical AIP features were explored., Results: PROMIS scores were significantly worse than the general population across all domains, except depression. Each domain discriminated well between asymptomatic and symptomatic patients with symptomatic patients having worse scores. Many important clinical variables like symptom frequency were significantly associated with domain scores in univariate analyses, showing responsiveness of the scales, specifically pain interference and fatigue. However, most regression models only explained ~20% of the variability observed in domain scores., Conclusion: Pain interference and fatigue were the most responsive scales in measuring QoL in this AIP cohort. Future studies should assess whether these scales capture longitudinal disease progression and treatment response.

The term ‘porphyria’ comes from the Greek ‘porphyra’. It refers to a heterogeneous group of metabolic disorders caused by the enzymatic deficiency in the biosynthesis of the heme group. Acute intermittent porphyria is caused by a deficiency of the porphobilinogen deaminase enzyme. A 40-year-old woman presented with abdominal pain for ten days (which required laparotomy that evidenced no surgical pathology), severe hydroelectrolytic disorder due to hyponatremia and resistant hypokalemia, persistent tachycardia and hypertension. Seven days later, she developed acute flabby quadriparesis and presented a single generalized tonic-clonic convulsive crisis. Neurophysiological studies supported mixed axonal polyneuropathy and urine results of porphobilinogen and porphyrins were elevated. After acute intermittent porphyria was diagnosed, hemin was administered, which stabilized the patient’s clinical signs and normalized the porphobilinogen. The prevalence of this entity is 1 in 2,000 people. It is an autosomal dominant disease, which affects mainly women between 20 and 40 years of age. This entity manifests with neurological and visceral symptoms. Management consists of hematin and dextrose administration avoiding hypotonic solutions because of the risk of exacerbating hyponatremia.

Background: Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10-20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown. Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks. Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C9*2, *3; CYP2C19*2; CYP2D6*4, *5; CYP3A4*1B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder mutation c.669&#95;698del30., Results: AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers (p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype., Conclusions: AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future.

Background: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks., Objective: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks., Methods: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs -/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients., Results: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence., Conclusion: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Background: Acute intermittent porphyria (AIP) is an autosomal recessive disorder with intermittent attacks. Patients with AIP are susceptible to impaired quality of life and psychological distress., Objectives: To document the clinical features of AIP and its impact on SF-36 and IES scores of AIP patients in China and to explore the variables associated with SF-36 and IES scores., Methods: A single investigator collated data related to treatments and outcomes in 27 patients with AIP of PUMCH. A cross-sectional questionnaire survey including the SF-36, the IES-R, and demographic questions was conducted in the north of China. Differences in the QoL scale/summary scores and proportions in the QoL dimensions between patients and the general population were analyzed. Independent effects of chronic conditions and demographic variables on the SF-36 and IES-R were analyzed., Results: AIP patients had considerably lower SF-36 scores than the general population (the PF score and MH were lower than normal, P < 0.05). Working had higher RP than staying at home ( P = 0.02); "without acute attack" had higher PF and BP scores and PCS composite score ( P = 0.001). The mean IES-R score of AIP was higher than normal (36.7 ± 11.8 points, P < 0.001), "without acute attack" had lower intrusion score than "with acute attack" ( P = 0.03)., Conclusion: AIP patients in China had impaired quality of life, especially in terms of physical health. The acute attacks coursed the posttraumatic stress disorder-related symptoms.

Acute intermittent porphyria (AIP) is a disease affecting the heme biosynthesis pathway caused by mutations of the hydroxymethylbilane synthase (HMBS) gene. AIP is thought to display autosomal dominant inheritance with incomplete penetrance. We evaluated the prevalence, penetrance and heritability of AIP, in families with the disease from the French reference center for porphyria (CFP) (602 overt patients; 1968 relatives) and the general population, using Exome Variant Server (EVS; 12 990 alleles) data. The pathogenicity of the 42 missense variants identified was assessed in silico, and in vitro, by measuring residual HMBS activity of the recombinant protein. The minimal estimated prevalence of AIP in the general population was 1/1299. Thus, 50 000 subjects would be expected to carry the AIP genetic trait in France. Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1% in the general population. Intrafamily correlation studies showed correlations to be strong overall and modulated by kinship and the area in which the person was living, demonstrating strong influences of genetic and environmental modifiers on inheritance. Null alleles were associated with a more severe phenotype and a higher penetrance than for other mutant alleles. In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS. An oligogenic inheritance model with environmental modifiers might better explain AIP penetrance and heritability.

Acute intermittent porphyria (AIP) has been associated with schizophrenia in some studies, but prior research is limited by the absence of comparison populations. Here, we linked Swedish registers to examine the risk of schizophrenia and bipolar disorder in 717 individuals diagnosed with AIP and their first-degree relatives, compared with matched individuals without AIP and their first-degree relatives. Individuals with AIP had a fourfold increased risk of schizophrenia or bipolar disorder. Similarly, relatives of individuals with AIP had double the risk of schizophrenia or bipolar disorder, suggesting that these associations may be as a result of common genetic influences., (© The Royal College of Psychiatrists 2015.)

Background and Objectives: Acute intermittent porphyria (AIP) is a rare disease that results from a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. AIP carriers are at risk of presenting acute neurovisceral attacks associated with overproduction of heme-precursors in the liver., Patients and Method: We report the characteristics of all AIP patients attended in the Hospital Clinic of Barcelona during the years 1993-2013 and their long-term follow-up., Results: Thirty-five AIP patients (33 women, 2 men) experienced acute attacks. Treatment with hemin resolved the acute neurovisceral crisis in all cases. Nine patients presented peripheral neuropathy and persistent sequelae. Long-term follow-up allowed classifying the patients into groups: A, patients with acute symptoms during 1-2 years and subsequent long-lasting clinical remission (n=24) or a few sporadic crises (n=3), and B, patients with recurrent attacks requiring chronic administration of hemin (n=8). In a majority of the patients of group A, the urinary excretion of heme-precursors decreased gradually over time. However, the chronic hemin regime did not induce a decline of urinary heme-precursors in the patients of group B. Additionally, we identified 44 asymptomatic AIP carriers, most (70.5%) with normal values of heme-precursors in urine., Conclusions: A majority of the AIP patients of our series achieved a long-lasting clinical remission. A minority (23%) presented recurrent attacks that required chronic hemin infusions without feasible interruption and without long-term biochemical remission. The type of mutation within the porphobilinogen deaminase gene and also life-style related factors may determine remission time-course., (Copyright © 2014 Elsevier España, S.L.U. All rights reserved.)

Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population-based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis.

The porphyrias are a group of rare metabolic disorders. The incidence and prevalence are low because the acute intermittent porphyria (AIP) is rare. Our aim was to assess the use of anthropometric and quality-of-life parameters in porphyric patients in order to identify predictor factors that might help in characterizing AIP patients.Sixteen AIP patients from Murcia (Spain) were recruited from local health centers in 2008 and 2009. A control group of 16 healthy people was established. Body composition was assessed by bioelectrical impedance analysis (BIA) and anthropometric measurements: body weight; height; knee-heel height; waist, hip, upper arm and calf circumferences (CCs); biacromion and biiliac diameters; bicondylar and biepicondylar width; and triceps, subscapular, supraspinale, and calf skinfold thickness. Anthropometric indicators were obtained from anthropometric measurements. A quality-of-life evaluation was carried out using the EuroQol-5D (EQ-5D) questionnaire and Barthel and Katz indexes. Significant differences in means were tested by unpaired Student t test. Group differences in anthropometric measurements were tested with a 2-way analysis of variance (group × condition: age group, overweight, and adiposity degree). Relative frequencies were obtained for noncontinuous variables. Significant differences in prevalence were calculated by means of χ.AIP patients showed statistically significant differences in terms of knee-heel height, biiliac diameter, CC, triceps skinfold thickness, BIA, ponderal index, endomorphy, and ectomorphy. Only 1 quality-of-life indicator, visual analog scale, in the EQ-5D questionnaire showed significant differences between porphyric and control groups.Some anthropometric parameters and the EQ-5D questionnaire could be used to appreciate the presence or follow the evolution of the disease in AIP patients.

Porphyrias are a group of metabolic diseases that arise from deficiencies in the heme biosynthetic pathway. A partial deficiency in hydroxymethylbilane synthase (HMBS) produces a hepatic disorder named Acute Intermittent Porphyria (AIP); the acute porphyria is more frequent in Argentina. In this paper we review the results obtained for 101 Argentinean AIP families and 6 AIP families from foreign neighbour countries studied at molecular level at Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP). Thirty-five different mutations were found, of which 14 were described for the first time in our population. The most prevalent type of mutations was the missense mutations (43%) followed by splice defects (26%) and small deletions (20%). An odd case of a double heterozygous presentation of AIP in a foreign family from Paraguay is discussed. Moreover, it can be noted that 38 new families were found carrying the most frequent mutation in Argentina (p.G111R), increasing to 55.66% the prevalence of this genetic change in our population and adding further support to our previous hypothesis of a founder effect for this mutation in Argentina. Identification of patients with an overt AIP is important because treatment depends on an accurate diagnosis, but more critical is the identification of asymptomatic relatives to avoid acute attacks which may progress to death.