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Background Acute hepatic porphyria (AHP) is a group of rare but treatable conditions associated with diagnostic delays of 15 years on average. The advent of electronic health records (EHR) data and machine learning (ML) may improve the timely recognition of rare diseases like AHP. However, prediction models can be difficult to train given the limited case numbers, unstructured EHR data, and selection biases intrinsic to healthcare delivery. We sought to train and characterize models for identifying patients with AHP. Methods This diagnostic study used structured and notes-based EHR data from 2 centers at the University of California, UCSF (2012-2022) and UCLA (2019-2022). The data were split into 2 cohorts (referral and diagnosis) and used to develop models that predict (1) who will be referred for testing of acute porphyria, among those who presented with abdominal pain (a cardinal symptom of AHP), and (2) who will test positive, among those referred. The referral cohort consisted of 747 patients referred for testing and 99 849 contemporaneous patients who were not. The diagnosis cohort consisted of 72 confirmed AHP cases and 347 patients who tested negative. The case cohort was 81% female and 6-75 years old at the time of diagnosis. Candidate models used a range of architectures. Feature selection was semi-automated and incorporated publicly available data from knowledge graphs. Our primary outcome was the F-score on an outcome-stratified test set. Results The best center-specific referral models achieved an F-score of 86%-91%. The best diagnosis model achieved an F-score of 92%. To further test our model, we contacted 372 current patients who lack an AHP diagnosis but were predicted by our models as potentially having it (≥10% probability of referral, ≥50% of testing positive). However, we were only able to recruit 10 of these patients for biochemical testing, all of whom were negative. Nonetheless, post hoc evaluations suggested that these models could identify 71% of cases earlier than their diagnosis date, saving 1.2 years. Conclusions ML can reduce diagnostic delays in AHP and other rare diseases. Robust recruitment strategies and multicenter coordination will be needed to validate these models before they can be deployed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Acute hepatic porphyrias (AHPs) are a family of rare, autosomal, dominantly inherited conditions characterized by abnormalities in the production of heme. Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway in patients with porphyria. In particular, the RNA interference therapeutic givosiran was approved for the treatment of adults and adolescents with AHP aged >12 years based on the positive results of the phase III trial ENVISION. Despite the extended characterization of the activity of givosiran in clinical trials, reports on the long-term effects and effectiveness of the treatment in clinical practice are still scant. To fill this gap, this case series describes a monocentric Italian cohort of AHP patients treated with givosiran. Overall, our real-life experience supports the clinical evidence that long-term treatment with givosiran is well tolerated and able to provide sustained and continuous benefit to patients with acute intermittent porphyria, as reflected by the reduction in the frequency of attacks. In our series, givosiran treatment was also associated with improvement in assessments of quality of life, pain and fatigue.

Background: Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP. Methods: We conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times ("high excretors"); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN). Results: During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy. Conclusion: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP. [ABSTRACT FROM AUTHOR]

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 μmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine β-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Introduction: Porphyria refers to a group of disorders associated with defects in heme synthesis. They can be associated with severely debilitating features, including abdominal pain, psychiatric symptoms, neurological defects, and cardiovascular irregularities. Although these diseases are rare, patients with attacks often do present to the emergency department (ED) where consideration of porphyria is generally not included in the differential.Case Report: Here, we examine a case of a 16-year-old male who presented to our ED for evaluation of recurring abdominal pain and auditory hallucinations in which porphyria was considered by the emergency physician.Discussion: Not considering acute porphyria in patients with recurring neurovisceral symptoms in the ED can lead to missed opportunities for diagnosing such pathologies.

Background: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. Results: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0–46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. Conclusions: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.

BackgroundAcute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP.MethodsWe conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times (“high excretors”); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN).ResultsDuring acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy.ConclusionThis study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.

Background & aimsAbdominal pain is the most common gastrointestinal symptom reported in ambulatory clinics, but little is known about its prevalence and burden of illness in the general community. We conducted a population-based survey to determine the epidemiology, clinical characteristics, and healthcare-seeking behavior of persons with abdominal pain.MethodsUsing an online survey research firm, we recruited a representative sample of adults (18 years or older) with a history of abdominal pain. The survey included questions about abdominal pain severity as measured by GI PROMIS (a validated patient-reported outcome questionnaire), healthcare-seeking behaviors, and tests performed to evaluate symptoms. We used multivariable regression models to adjust for confounding.ResultsOverall, 24,929 individuals accessed the survey and 10,300 respondents reported experiencing abdominal pain and completed the questionnaire. Most participants (81.0%) were symptomatic in the past week, as measured by GI PROMIS. Of participants with prior pain, 61.5% sought medical care for their symptoms; non-Hispanic Blacks, Latinos, and participants with more education, insurance, a usual source of care, comorbidities, and more severe pain had increased odds for seeking care. Participants who sought care consulted with the following providers: primary care physicians (84.5%), gastroenterologists (39.2%), nurse practitioners or physician assistants (18.6%), obstetricians or gynecologists (8.3%), general surgeons (7.1%), or rheumatologists (3.2%). Moreover, 72.4% of healthcare seekers received tests to evaluate their pain: cross-sectional imaging (54.2%), colonoscopy (52.3%), upper endoscopy (40.8%), exploratory surgery (6.3%), or capsule endoscopy (5.0%).ConclusionsThe burden of illness and healthcare use associated with abdominal pain is high in the United States. However, 2 of 5 individuals did not seek care for their symptoms and many of them might have undiagnosed, treatable disorders.

Abstract Background Porphyrias are a rare group of disease due to inherited defects of heme synthesis with important systemic manifestations and great burden of disease for patients and families due to the exceptional course of disease with disabling chronic symptoms interposed by life-threatening acute attacks. Unfortunately, the porphyrias are usually underrecognized reflecting a lack of medical and disease awareness as well as few studies about natural history in large cohorts of patients. The main aim of this article is present consistent data about natural history and burden of disease in a large Brazilian cohort. Methods We conducted a national cross-sectional registry with retrospective clinical data of Brazilian patients with porphyria collected with Brazilian patients Association with Porphyria in collaboration with a tertiary care center for rare diseases. Results A cohort of 172 patients was analyzed in which 148 (86%) patients had the diagnosis of acute hepatic porphyria [AHP] that needed a mean of 62.04 medical visits and 9.6 years to achieve a definitive diagnosis. About AHP cohort, the most common first clinical manifestation were abdominal pain in 77 (52%) patients and acute muscle weakness in 23 (15.5%) with 73 (49.3%) patients presenting only one attack during disease course and 37 (25%) exhibiting 4 or more attacks in the last year. Of note, 105 patients with AHP reported chronic manifestations and the scores for quality of life are lower when compared with general healthy population. Conclusions Brazilian patients with AHP had a higher prevalence of chronic disabling manifestations and a poor quality of life like other cohorts and a higher proportion of patients with recurrent attacks than previously reported.

Abstract Acute hepatic porphyria (AHP) is a group of rare genetic diseases of heme biosynthesis resulting in severe neurovisceral attacks and chronic complications that negatively impact patients' well‐being. This study evaluated the impacts of AHP on patients' physical and emotional health from a global perspective. Adult patients from the United States, Italy, Spain, Australia, Mexico, and Brazil with AHP with >1 porphyria attack within the past 2 years or receiving intravenous hemin and/or glucose for attack prevention completed an online survey assessing demographics, health characteristics, and patient‐reported outcomes. Results were analyzed collectively and by patient subgroups. Ninety‐two patients with AHP across the six countries completed the survey. More than 70% of patients reported that their physical, emotional, and financial health was fair or poor. Among patients who reported pain, fatigue, and muscle weakness, 94.3%, 95.6%, and 91.4%, respectively, reported that these symptoms limited daily activities. Moderate to severe depression was present in 58.7% of patients, and moderate to severe anxiety in 48.9% of patients. Of the 47% of patients who were employed, 36.8% reported loss in productivity while at work. Among patients, 85.9% reported that they had to change or modify goals that were important to them because of AHP. Aside from differences in healthcare utilization and pain severity, scores did not significantly vary with attack rate or use of hemin or glucose prophylactic treatments. AHP substantially impacts patients' physical and emotional well‐being, regardless of hemin or glucose prophylactic treatment or frequency of attacks. This multinational study demonstrates that there is substantial disease burden for patients with AHP, even among those experiencing sporadic attacks or using prophylactic treatment.

Current knowledge of pregnancy and perinatal outcomes in women with acute hepatic porphyria (AHP) is largely based on biochemical disease models, case reports, and case series. We performed a nationwide, registered‐based cohort study to investigate the association between maternal AHP and the risk of adverse pregnancy and perinatal outcomes. All women in the Swedish Porphyria Register with confirmed AHP aged 18 years or older between 1987 and 2015 and matched general population comparators, with at least one registered delivery in the Swedish Medical Birth Register were included. Risk ratios (RRs) of pregnancy complications, delivery mode and perinatal outcomes were estimated and adjusted for maternal age at delivery, area of residency, birth year and parity. Women with acute intermittent porphyria (AIP), the most common form of AHP, were further categorized according to maximal lifetime urinary porphobilinogen (U‐PBG) levels. The study included 214 women with AHP and 2174 matched comparators. Women with AHP presented with a higher risk for pregnancy‐induced hypertensive disorder (aRR 1.73, 95% CI 1.12–2.68), gestational diabetes (aRR 3.41, 95% CI 1.69–6.89), and small‐for‐gestational‐age birth (aRR 2.08, 95% CI 1.26–3.45). In general, RRs were higher among women with AIP who had high lifetime U‐PBG levels. Our study shows an increased risk for pregnancy induced hypertensive disease, gestational diabetes, and small for gestational age births for AHP women, with higher relative risks for women with biochemically active AIP. No increased risk for perinatal death or malformations was observed. [ABSTRACT FROM AUTHOR]

Patients suffering from different forms of acute hepatic porphyria present a high risk of primary liver cancer, specifically hepatocellular carcinoma and cholangiocarcinoma, determined by the activity of the disease even though an exact mechanism of carcinogenesis has not been recognized yet. Here, we present the clinical case of a 72-year-old woman who, approximately 29 years after the diagnosis of acute intermittent porphyria, presented with intrahepatic cholangiocarcinoma with a histological diagnosis of adenocarcinoma starting from the biliary-pancreatic ducts, which was diagnosed during the clinical and anatomopathological evaluation of a pathological fracture of the femur. [ABSTRACT FROM AUTHOR]

Background: Porphyrias are a rare group of disease due to inherited defects of heme synthesis with important systemic manifestations and great burden of disease for patients and families due to the exceptional course of disease with disabling chronic symptoms interposed by life-threatening acute attacks. Unfortunately, the porphyrias are usually underrecognized reflecting a lack of medical and disease awareness as well as few studies about natural history in large cohorts of patients. The main aim of this article is present consistent data about natural history and burden of disease in a large Brazilian cohort. Methods: We conducted a national cross-sectional registry with retrospective clinical data of Brazilian patients with porphyria collected with Brazilian patients Association with Porphyria in collaboration with a tertiary care center for rare diseases. Results: A cohort of 172 patients was analyzed in which 148 (86%) patients had the diagnosis of acute hepatic porphyria [AHP] that needed a mean of 62.04 medical visits and 9.6 years to achieve a definitive diagnosis. About AHP cohort, the most common first clinical manifestation were abdominal pain in 77 (52%) patients and acute muscle weakness in 23 (15.5%) with 73 (49.3%) patients presenting only one attack during disease course and 37 (25%) exhibiting 4 or more attacks in the last year. Of note, 105 patients with AHP reported chronic manifestations and the scores for quality of life are lower when compared with general healthy population. Conclusions: Brazilian patients with AHP had a higher prevalence of chronic disabling manifestations and a poor quality of life like other cohorts and a higher proportion of patients with recurrent attacks than previously reported. [ABSTRACT FROM AUTHOR]

Background and aims: Orphan diseases, or rare diseases, are defined in Europe as diseases that affect less than 5 out of every 10,000 citizens. Given the small number of cases and the lack of profit potential, pharmaceutical companies have not invested much in the development of possible treatments. However, over the last few years, new therapies for rare diseases have emerged, giving physicians a chance to offer personalized treatment. With this paper, we aim to present some of the orphan neurological diseases for which new drugs have been developed lately. Methods: We have conducted a literature review of the papers concerning rare diseases and their treatment, and we have analyzed the existing studies for each orphan drug. For this purpose, we have used the Google Scholar search engine and the Orphanet. We have selected the studies published in the last 15 years. Results. Since the formation of the National Organization for Rare Diseases, the Orphan Drug Act, and the National Institutes of Health Office of Rare Diseases, pharmacological companies have made a lot of progress concerning the development of new drugs. Therefore, diseases that until recently were without therapeutic solutions benefit today from personalized treatment. We have detailed in our study over 15 neurological and systemic diseases with neurological implications, for which the last 10–15 years have brought important innovations regarding their treatment. Conclusions: Many steps have been taken towards the treatment of these patients, and the humanity and professionalism of the pharmaceutical companies, along with the constant support of the patient's associations for rare diseases, have led to the discovery of new treatments and useful future findings. [ABSTRACT FROM AUTHOR]

Abstract Background Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. Results Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0–46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. Conclusions Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.

Abstract Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, $$\delta$$ δ -aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

High mortality rates have been reported in historical cohorts of acute intermittent porphyria (AIP) patients. The mortality associated with (hydroxymethylbilane synthase) HMBS variant heterozygosity is unknown. This study estimates all-cause mortality in pedigrees with HMBS gene variants that cause AIP. We collected data on the lifespan of individuals in Dutch AIP pedigrees and performed analyses using the family tree mortality ratio method. This gave us standardized mortality ratios for these pedigrees compared to the Dutch general population as a primary outcome. Between 1810 and 2017, the overall mortality in these pedigrees was identical to that of the general Dutch population: (SMR 1.01, p = 0.441). However, compared with the general population the SMR was significantly higher in women aged 45–64 years (SMR 1.99, p = 0.00003), which was based on excess mortality between 1915 and 1964 (SMR 1.94, p < 0.00002). In men aged 70–74 years, the SMR was 1.55 (p = 0.0021), based on excess mortality that occurred between 1925 and 1964 (SMR 1.92, p = 0000000003). Overall, mortality from HMBS variant heterozygosity was not increased compared with the general population. Severe excess mortality occurred in young women and old men between 1915 and 1964. Heterozygotes reached a normal lifespan during the past half-century, in parallel with disease awareness and the prevention of new attacks through family counselling. [ABSTRACT FROM AUTHOR]

Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes., (© 2024 SSIEM.)

Background: Acute Hepatic Porphyria is a group of four rare genetic but treatable diseases that often go undiagnosed due to its non-specific symptoms, under-recognition of the condition by clinicians, and the lack of access to specialists and appropriate testing. This case-control study investigates the phenotypic and demographic patterns in Acute Hepatic Porphyria (AHP) patients at a tertiary care center (University of California Los Angeles) to update recommendations for recognition and diagnosis of this disease in our community., Method: A retrospective chart analysis was conducted on 45 patients who were evaluated for AHP, Electronic Medical Record (EMR) data was collected and analyzed to investigate clinical differences and correlations., Results: 27 patients tested positive for AHP through urinary metabolites and confirmatory genetic testing and 18 patients tested negative; of those, 16 patients received a definite alternative diagnosis. Hashimoto's, T1DM (Type 1 Diabetes Mellitus), Fibromyalgia and cannabinoid use with cyclic vomiting syndrome were negatively correlated with AHP, while psychiatric disorders and OBGYN disorders were positively correlated with AHP. The highest rate of diagnosis resulted from a combination of genetic and biochemical testing. Testing outside of an acute attack was not associated with a positive diagnosis., Conclusions: Patients with a history of OBGYN disorders and psychiatric disorders may be at increased risk of having AHP, yet there is a lack of involvement of these specialties in the diagnosis and care of AHP, in addition to a lack of studies investigating AHP in non-white populations potentially leading to reduced recognition of AHP., Competing Interests: VR receives grant funding from Alnylam, Genentech, Merck, Takeda, Blueprint Medicines, Stryker, and Mitsubishi Tanabe. The authors declare that no actual conflicts of interest exist. The other authors hereby declare that they have no potential competing conflicts of interest.

Eslicarbazepine acetate, a third-generation antiepileptic drug (AED), has shown improved clinical response and safety in comparison to older generation AEDs for patients with partial-onset seizures. It is currently not known whether eslicarbazepine acetate is safe to use in patients with the acute hepatic porphyrias (AHPs) since a few first-generation AEDs, such as phenobarbital and carbamazepine, are known porphyrogenic agents. In this study, we used a recently published in vitro fluorescence-based screening assay to screen for porphyrogenicity in various agents. The assay confirmed that among the tested compounds used, allyl isopropyl acetamide, carbamazepine, eslicarbazepine acetate, and phenobarbital were porphyrogenic. Thus, eslicarbazepine acetate should be avoided if possible in patients with the AHPs, but if initiated, patients should be closely monitored and the drug should be discontinued if a porphyric exacerbation occurs. [ABSTRACT FROM AUTHOR]

Introduction: Acute hepatic porphyria (AHP) is a family of rare metabolic diseases characterized by potentially life-threatening acute attacks and, in some patients, chronic debilitating symptoms. While patients with frequent or recurrent attacks (three or more attacks annually) are known to have reduced health-related quality of life (HRQoL) as most aspects of daily living are impacted, limited data exist in patients with sporadic attacks. This research aims to identify porphyria-related symptoms between attacks, characterize the frequency, severity, and bothersomeness of these symptoms, and more generally understand the burden of this disease in patients who experience attacks sporadically.Methods: Patients with AHP with sporadic attacks (AHP-SA) (at least one porphyria attack in the past 2 years, but no more than two attacks per year in the previous 2 years) were recruited, via outreach performed by patient advocacy groups, for participation in qualitative telephone interviews. Interviews were conducted using a semi-structured guide and were audio-recorded, transcribed, anonymized, coded, and analyzed to determine if saturation was reached.Results: A total of 14 participants with AHP-SA were interviewed (mean age 45 years, 100% female). The most frequently reported chronic symptoms were fatigue, pain, heartburn, and constipation. The most frequently experienced chronic impacts were difficulty performing daily activities, difficulty exercising, negative impact on work, need for a special diet, anxiety, and depression. Beyond these chronic symptoms and impacts, participants also frequently described flares in their porphyria that were severe, did not qualify in their minds as an acute attack, but were nonetheless more severe than their typical chronic experience.Conclusion: Patients with acute hepatic porphyria who experience sporadic attacks face significant chronic symptoms and impacts that frequently require significant pharmacological and clinical treatment. The reported severity of these symptoms and impacts suggests that the humanistic burden of AHP-SA is substantial and may lead to a significant decrease in health-related quality of life in these patients between acute attacks. The presence of flares that do not reach the level of what is considered an acute attack by patients is a unique finding of this study not reported elsewhere and requires additional investigation. [ABSTRACT FROM AUTHOR]

Eslicarbazepine acetate, a third-generation antiepileptic drug (AED), has shown improved clinical response and safety in comparison to older generation AEDs for patients with partial-onset seizures. It is currently not known whether eslicarbazepine acetate is safe to use in patients with the acute hepatic porphyrias (AHPs) since a few first-generation AEDs, such as phenobarbital and carbamazepine, are known porphyrogenic agents. In this study, we used a recently published in vitro fluorescence-based screening assay to screen for porphyrogenicity in various agents. The assay confirmed that among the tested compounds used, allyl isopropyl acetamide, carbamazepine, eslicarbazepine acetate, and phenobarbital were porphyrogenic. Thus, eslicarbazepine acetate should be avoided if possible in patients with the AHPs, but if initiated, patients should be closely monitored and the drug should be discontinued if a porphyric exacerbation occurs.

Abstract Background This study used quantitative and qualitative research methods to analyze how acute hepatic porphyria (AHP) affects patients with varying annualized porphyria attack rates. The overall impact of AHP on patients and caregivers, including their quality of life, was explored. The nature and treatment of acute attacks, experiences of long-term heme arginate treatment and access to other appropriate treatment, and the extent of and treatment for chronic symptoms were also investigated within this study. Methods Patient and caregiver data were collected via an online survey of members of the British Porphyria Association, followed by an optional 1-h telephone interview. Results Thirty-eight patients and 10 caregivers responded to the survey. Of those, 10 patients and three caregivers completed follow-up interviews. Overall, 19 patients (50%) had experienced an acute attack within the previous 2 years, and the severity and types of symptoms experienced during or between acute attacks varied considerably. There were no clear definitions among patients for ‘mild’ or ‘severe’ attacks. Treatments and treatment settings used to manage attacks also varied. Following unsatisfactory care experiences at hospitals, some patients reported avoiding further hospital services for later attacks. Therefore, using settings of care as a measure of attack severity should be avoided. Ninety-four percent of patients also experienced chronic symptoms, which were as varied as acute attacks. Pain was the predominant chronic symptom and was managed with opioids in severe cases. Regardless of AAR, porphyria heavily impacted the daily lives of patients and caregivers. Although patients experiencing frequent attacks generally endured a greater impact on their daily life, patients with less frequent attacks also experienced impacts on all domains (social, leisure activities, relationship with family, relationships, psychological wellbeing, finances, employment, and study). Caregivers were most affected in the finance, relationships with family, and employment domains, and just over half of the caregivers reported a moderate impact on their psychological wellbeing. Conclusions/implications The burden of illness with AHP is high across all patients, regardless of frequency of attacks, and AHP negatively affects patients and caregivers alike.

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, [Formula: see text]-aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations. [ABSTRACT FROM AUTHOR]

Background: Acute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include acute attacks, occurring mainly among female patients. This study describes the diversity of acute symptoms, changes in triggering factors and life expectancy among female patients during the past five decades. Methods: 107 Finnish female patients were enrolled into a retrospective, longitudinal study during 2015. Clinical, biochemical and genetic data was obtained from the medical reports, registry data and a questionnaire designed for the study. Causes of death were studied in additional 32 female patients. Results: Of the 43 patients with hospitalization, 33% had non-complicated, 35% prolonged and 28% severe attacks with no correlation with the disease-causing mutation. Of the deceased patients, 31% died of an acute attack during 1957–1979. Thereafter the incidence and severity of acute attacks have decreased substantially. 55% of the subjects reported acute symptoms (dysautonomia and mental symptoms) without hospitalization, 29% had porphyria symptoms >10 times, and 23% within the last year. Despite 22% of the female patients had died of primary liver cancer, the life expectancy increased more than 10 years during the follow-up, and did not differ from the normal population at present. Conclusions: The incidence of acute attacks requiring hospitalization has decreased, but more than half of the female patients reported acute symptoms affecting their well-being. Symptoms are currently triggered by hormonal changes and weight loss emphasizing the importance of early recognition and active management to avoid disease exacerbation. Death due to primary liver cancer is common and should be screened regularly.

Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder caused by decreased activity of the enzyme porphobilinogen deaminase in the heme synthesis pathway. This leads to the accumulation of toxic porphyrin precursors, such as porphobilinogen and δ-aminolevulinic acid. Clinical manifestations typically include episodic bouts of severe neurovisceral pain and autonomic dysfunction. These events have various triggers, including fasting, dehydration, hormonal fluctuations, and certain medications, while treatment involves dextrose infusions for mild attacks and intravenous hemin for severe cases. This case highlights a 17-year-old female patient with numerous prior presentations to the healthcare system for intense bouts of abdominal pain, vomiting, and seizure-like activity who was ultimately diagnosed with AIP. Her course was complicated by diagnostic delays and challenges managing severe refractory pain requiring prolonged courses of hemin in addition to a multimodal pain plan. This case highlights the diagnostic complexities and treatment challenges that patients with AIP face when navigating this challenging clinical syndrome and identifies an opportunity for increased awareness to guide the testing and treatment for AIP., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rudnick et al.)

Background: Pregnancy in women with acute hepatic porphyria (AHP) has historically been associated with significant morbidity. Clinical outcomes have been the focus of previous reports on porphyria and maternal health, with little data available on the levels of heme precursors during pregnancy. We present the results of a follow‐up program for women with AHP in the Swedish cohort who were pregnant between 2001 and 2020. Methods: Thirty‐three women with AHP were monitored during 44 pregnancies resulting in 44 single births. Seven of 33 women had a clinical history of acute attacks that required hospitalization. Results: Four women experienced acute porphyria attacks during pregnancy and one during the puerperium. Seven women developed hypertension and four pregnancies ended with pre‐eclampsia. There were no maternal or fetal pre‐ or postnatal deaths. One infant had a congenital cardiac anomaly. In 32 of the 38 pregnancies in which we measured heme precursors in the urine during pregnancy, the levels increased. Conclusion: Our observations align with contemporary reports that pregnancy in patients with AHP is frequently uncomplicated. Excretion of heme precursors increased during pregnancy, but this did not manifest as a higher frequency of clinical porphyria manifestations. The involvement of porphyria specialists in the patients' maternal care is recommended for reducing risk and improving the probability of good pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Background & Aims: Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria. Methods: Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. Results: Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period. Conclusions: Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life. [ABSTRACT FROM AUTHOR]

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options. [ABSTRACT FROM AUTHOR]

Introduction: Acute porphyrias are rare disorders of the heme biosynthetic pathway and present with acute neurovisceral symptoms that can be induced by hormonal changes and medications. Women are far more likely to present with clinical symptoms than men, particularly during parts of their lifetime with changes in the level of female sex hormones such as ovulation, menstruation, and pregnancy. Treatment of ovulatory dysfunction and controlled ovarian hyperstimulation require the administration of hormones, which are considered porphyrinogenic. Women with acute hepatic porphyria have therefore been considered unsuitable for such treatments in the past. Material and methods: We report on nine women with acute hepatic porphyria who underwent in vitro fertilization (IVF), preceded by ovarian stimulation. Their mean age at the start of IVF was 33.2 years (range 27–38 years). Two women had been diagnosed with polycystic ovarian syndrome, two were treated for hyperprolactinemia, two had hypothyroidism, of which one also had type 1 diabetes, one had a uterus malformation, one had anovulatory cycles, and one used a sperm donor. Results: All patients were able to undergo fertility treatment without experiencing severe porphyria attacks. Conclusions: Women with acute hepatic porphyria considering fertility treatments should be assessed individually for potential risks, treatment should be planned in close collaboration with a porphyria specialist, and biochemical activity should be monitored regularly during ovarian stimulation. As we gather more knowledge, we hope that the porphyrinogenicity of the stimulation agents is re‐assessed and that more studies will shed light on the reproductive health of women living with acute hepatic porphyria. [ABSTRACT FROM AUTHOR]

Abstract Background Acute hepatic porphyria (AHP) consists of three rare metabolic disorders. We investigated the risk of long-term sick leave, disability pension, and premature death in individuals with AHP compared to the general population. Methods In a nationwide cohort study from 1992 to 2017, records of 333 persons (total person-years = 6728) with a confirmed AHP diagnosis were linked to several national compulsory registries (reference population = 5,819,937). We conducted survival analyses to assess additional risk. Results Persons with AHP had higher risks of accessing long-term sick leave (adjusted hazard ratio (aHR): 1.5, 95% confidence interval (CI): 1.3, 1.7) and disability pension (aHR: 1.9, CI: 1.5, 2.4). The risk was highest in persons who had been hospitalised for acute attacks, while no additional risk was observed in asymptomatic AHP gene mutation carriers. The median age when accessing disability pension was 45 years, 21 years younger than the general population. AHP was associated with increased risk of mortality due to hepatocellular carcinoma (adjusted mortality rate ratio (aMRR): 84.4, CI: 37.8, 188.2), but no overall increased risk of premature death was observed. Conclusions Persons with symptomatic AHP were at increased risk of accessing long-term sick leave and disability pension but not of premature death.

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain‐Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta‐aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: This study used quantitative and qualitative research methods to analyze how acute hepatic porphyria (AHP) affects patients with varying annualized porphyria attack rates. The overall impact of AHP on patients and caregivers, including their quality of life, was explored. The nature and treatment of acute attacks, experiences of long-term heme arginate treatment and access to other appropriate treatment, and the extent of and treatment for chronic symptoms were also investigated within this study.Methods: Patient and caregiver data were collected via an online survey of members of the British Porphyria Association, followed by an optional 1-h telephone interview.Results: Thirty-eight patients and 10 caregivers responded to the survey. Of those, 10 patients and three caregivers completed follow-up interviews. Overall, 19 patients (50%) had experienced an acute attack within the previous 2 years, and the severity and types of symptoms experienced during or between acute attacks varied considerably. There were no clear definitions among patients for 'mild' or 'severe' attacks. Treatments and treatment settings used to manage attacks also varied. Following unsatisfactory care experiences at hospitals, some patients reported avoiding further hospital services for later attacks. Therefore, using settings of care as a measure of attack severity should be avoided. Ninety-four percent of patients also experienced chronic symptoms, which were as varied as acute attacks. Pain was the predominant chronic symptom and was managed with opioids in severe cases. Regardless of AAR, porphyria heavily impacted the daily lives of patients and caregivers. Although patients experiencing frequent attacks generally endured a greater impact on their daily life, patients with less frequent attacks also experienced impacts on all domains (social, leisure activities, relationship with family, relationships, psychological wellbeing, finances, employment, and study). Caregivers were most affected in the finance, relationships with family, and employment domains, and just over half of the caregivers reported a moderate impact on their psychological wellbeing.Conclusions/implications: The burden of illness with AHP is high across all patients, regardless of frequency of attacks, and AHP negatively affects patients and caregivers alike. [ABSTRACT FROM AUTHOR]

The article describe the pathophysiology, clinical presentation and management of an acute attack of porphyria, including the appropriate use of haemarginate (HA). It discuss the perioperative considerations for managing patients with latent or active porphyria presenting for elective and emergency surgery.

Background: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients., Material and Methods: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP., Results: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP., Conclusions: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Acute hepatic porphyria (AHP) consists of three rare metabolic disorders. We investigated the risk of long-term sick leave, disability pension, and premature death in individuals with AHP compared to the general population.Methods: In a nationwide cohort study from 1992 to 2017, records of 333 persons (total person-years = 6728) with a confirmed AHP diagnosis were linked to several national compulsory registries (reference population = 5,819,937). We conducted survival analyses to assess additional risk.Results: Persons with AHP had higher risks of accessing long-term sick leave (adjusted hazard ratio (aHR): 1.5, 95% confidence interval (CI): 1.3, 1.7) and disability pension (aHR: 1.9, CI: 1.5, 2.4). The risk was highest in persons who had been hospitalised for acute attacks, while no additional risk was observed in asymptomatic AHP gene mutation carriers. The median age when accessing disability pension was 45 years, 21 years younger than the general population. AHP was associated with increased risk of mortality due to hepatocellular carcinoma (adjusted mortality rate ratio (aMRR): 84.4, CI: 37.8, 188.2), but no overall increased risk of premature death was observed.Conclusions: Persons with symptomatic AHP were at increased risk of accessing long-term sick leave and disability pension but not of premature death. [ABSTRACT FROM AUTHOR]

Acute intermittent porphyria (AIP) is the most common and severe form of porphyrias. This is a dominant inherited disorder with low penetrance, caused by mutations in gene coding hydroxymethylbilane synthase (HMBS). We present the results of our long‐term genetic study of AIP patients and their relatives (N = 153 and 302, respectively). We detected 88 HMBS gene mutations, 24 of which never described before. To identify additional factors conditioning AIP manifestation, we carried out whole exome sequencing on the group of AIP patients (N = 6). Mutation spectra of different patients virtually did not overlap. In 5 out of 6 patients, we found defects in genes regulating nervous system (UNC13A, ALG8, FBXO38, AGRN, DOK7, SCN4A). As usually acute AIP attacks have various neurological symptoms, we proposed a hypothesis of possible contribution of mutations in such genes in AIP manifestation. [ABSTRACT FROM AUTHOR]

Background: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP., Results: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload., Conclusions: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Background: Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published.Objectives: Our aim was to investigate the risk of PLC and other cancers in persons with AHP using a nationwide cohort design. Given that greater numbers of women than men tend to have manifest and more severe AHP, a further aim was to investigate sex differences in this risk.Methods: The study sample consisted of all Norwegian residents aged 18 years or older during the period 2000-2011. Persons with AHP (n = 251) were identified through the Norwegian Porphyria Centre, and patients with a cancer diagnosis were identified by linkage to the Cancer Registry of Norway.Results: For persons with AHP, the annual incidence rate of PLC was 0.35%. PLC risk was substantially higher for individuals with an AHP diagnosis compared to the reference population [adjusted hazard ratio (aHR) 108, 95% confidence interval (CI) 56-207]. In a meta-analysis of published studies on PLC and AHP, including ours, women had a higher risk than men. In addition, our results suggested that persons with AHP may have increased risks of kidney (aHR 7.4, 95% CI 2.4-23.1) and endometrial cancers (aHR 6.2, 95% CI 2.0-19.3).Conclusions: Our findings confirmed a substantially higher risk of PLC associated with AHP compared to the general population. In a meta-analysis, the risk was shown to be greater for women than men. The novel findings of a moderate to substantial association between AHP and kidney and endometrial cancers should be investigated further. [ABSTRACT FROM AUTHOR]