Reproductive health across the lifespan in acute hepatic porphyria

Onset of acute hepatic porphyria (AHP) in children/adolescents is very rare. The diagnosis is complex and challenging, most importantly due symptoms overlapping with those of other more common diseases. Treatment with porphyrinogenic drugs increases the risk of acute life-threatening attacks with potentially irreversible neurological sequelae. Herein, we report on afemale adolescent with AHP presenting with aplethora of clinical symptoms, including hyponatremia, seizure, rhabdomyolysis, arterial hypertension and neuropsychiatric symptoms. Paediatricians should therefore be aware of AHP and consider it in their differential diagnosis.

Pediatric Liver Diseases: Next-Generation Therapies.

Recommendations for recognizing and diagnosing Acute Hepatic Porphyria in atypical patient populations

ABSTRACT Acute hepatic porphyria (AHP) is a rare genetic disorder resulting from disruptions in hepatic heme biosynthesis, leading to the accumulation of neurotoxic porphyrins, aminolevulinic acid (ALA) and porphobilinogen (PBG). This accumulation causes acute and chronic neurovisceral symptoms, significantly affecting patient quality of life. Diagnosis is often delayed due to the rarity and nonspecific presentation of AHP, with biochemical and genetic testing serving as key diagnostic tools. For patients with recurrent attacks, prophylactic strategies aim to reduce episode frequency and severity. Although intravenous hemin remains the primary treatment for acute attacks, a major advancement in AHP management is givosiran, a small interfering ribonucleic acid therapy that reduces ALAS1 expression, thereby lowering ALA and PBG levels and decreasing attack frequency. Results from the ENVISION trial demonstrated a 70% reduction in porphyria attacks among patients receiving givosiran compared with placebo, leading to its Food and Drug Administration approval in 2019. Effective management of AHP includes addressing complications such as chronic pain, fatigue, neuropathy, and an increased risk of primary liver cancer. Patient education, medication management, and preventive strategies, including trigger avoidance and early symptom recognition, are critical in improving outcomes. Support groups and patient advocacy networks provide additional resources to enhance disease coping and adherence to care plans. With early diagnosis and comprehensive management, individuals with AHP can mitigate complications and maintain a better quality of life.

<i>Not So Benign</i>Acute Hepatic Porphyria: Rare, Potentially Devastating Disorders of Heme Biosynthesis

Objective: The prevalence of acute hepatic porphyria (AHP) in Japan is unknown. To diagnose AHP, identifying populations with a high prevalence of AHP is essential. We focused on non-specific abdominal pain (NSAP); however, the criteria for NSAP vary across studies. Therefore, this study aimed to investigate the diagnostic process of undiagnosed abdominal pain in general medicine clinical practice before proposing a definition of NSAP. In addition, we aimed to examine the potential AHP-related symptoms and implementation of AHP testing in these patients. AHP is a rare but fatal and treatable disease; hence, its early diagnosis is essential.Design: This retrospective observational study was conducted in the general medicine departments of six medical institutions in Japan over a 3-year period beginning on April 1, 2019.Participants: Patients with abdominal pain who underwent abdominal imaging examinations were included.Main outcome measures: The primary outcome was to characterize patients with undiagnosed abdominal pain. In addition, this study aimed to identify situations where physicians attempt to diagnose AHP in patients with abdominal pain.Results: Of the 1915 eligible participants, 317 (16.6%) had undiagnosed abdominal pain, and none of them were diagnosed with AHP in diagnosed abdominal pain. The median patient age was 55 years, and 134 patients were male. Multivariate logistic analysis revealed that hospitalization, dull pain, and the absence of depressive symptoms were associated with abdominal pain. All patients with undiagnosed abdominal pain demonstrated two to four indicative symptoms of AHP. However, none underwent urinalysis for a definitive diagnosis of AHP.Conclusions: Depressive symptoms and the absence of dull pain were associated with undiagnosed abdominal pain. Hospitalization for examination contributed to improving the diagnosis of abdominal pain. Despite the presence of indicative symptoms, urinary markers for AHP diagnosis were not measured. Establishing a diagnostic strategy for undiagnosed abdominal pain would provide better opportunities for patients with NSAP and could help shorten the diagnostic journey for those with rare diseases such as AHP.

ABSTRACTBackground and AimsThis study aimed to characterise symptoms and assess the prevalence of elevated urine porphyrin precursors in first‐degree relatives of acute hepatic porphyria (AHP) patients who have never experienced acute attacks and had no previous AHP genetic or biochemical testing.Methods149 first‐degree relatives of confirmed AHP patients, previously unscreened for the family mutation, were recruited. All underwent genetic analysis, with 143 completing a study questionnaire and 118 undergoing urine analysis for delta aminolevulinic acid (ALA) and porphobilinogen (PBG). The questionnaire focused on symptoms, medical and family history, and quality of life.ResultsThe study included 79 AHP mutation carriers and 70 non‐carriers. Carriers had significantly higher ALA (6.98 vs. 2.21 mg/g creatinine) and PBG levels (9.17 vs. 1.31 mg/g creatinine) than non‐carriers. Female carriers showed higher ALA (9.29 vs. 3.07 mg/g creatinine) and PBG levels (12.71 vs. 3.16 mg/g creatinine) than male carriers. Porphyria‐related symptoms were reported by 27% (21/77) of carriers compared to 15% (10/66) of non‐carriers, with carriers more likely to report dark urine and prolonged symptoms. Finally, 30.8% of carriers were asymptomatic high excreters (ASHE) with PBG levels exceeding four times the upper limit of normal (ULN).ConclusionsSignificant differences in porphyrin precursor excretion and symptom profiles were found between AHP mutation carriers and controls, as well as between female and male carriers. Female carriers are more likely to excrete porphyrin metabolites above the normal range. A larger than expected number of undiagnosed carriers are ASHE with levels greater than four times the ULN.

Acute hepatic porphyria (AHP), a rare genetic disorder, causes life-threatening porphyria attacks and chronic pain and impairs daily functioning and quality of life. Recently, a new siRNA therapy, givosiran, became available for AHP. This open-label, multicenter, single-arm study expanded access to givosiran and further explored its safety and efficacy in 10 Japanese patients with AHP. Participants received monthly subcutaneous injections of givosiran (2.5 mg/kg). Three patients were continued from the phase III ENVISION study of givosiran, and seven were newly recruited. Assessments comprised clinical AHP features, urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, use of hemin to treat attacks, and the Givosiran Patient Experience Questionnaire (GPEQ). Urinary ALA and PBG levels remained at or below upper limits of normal levels throughout the study. The GPEQ showed symptomatic improvement in eight participants. Of the eight adverse events, five were deemed by the investigator to be related to givosiran. One patient experienced two attacks, which required urgent healthcare visits but no hemin use. Generally, the safety profile was consistent with that previously observed. All adverse events were nonserious, and no deaths occurred. The study indicates that monthly givosiran administration is safe and clinically useful in Japanese patients with AHP.

Unexpected presentation of a first episode of acute hepatic porphyria (AHP) presenting with severe hyponatremia, seizure, severe rhabdomyolysis, arterial hypertension and posterior reversible encephalopathy syndrome (PRES) in a female adolescent

SAT-352 Genetic and epidemiological profile of a large brazilian cohort of acute hepatic porphyria

1278: PATIENT DEMOGRAPHICS AND CLINICAL CHARACTERISTICS AT ENROLMENT IN ELEVATE, AN INTERNATIONAL REGISTRY OF ACUTE HEPATIC PORPHYRIA

1279: DIMENSION ANALYSIS OF EQ-5D IN PATIENTS WITH ACUTE HEPATIC PORPHYRIA CATEGORIZED BY ANNUALIZED ATTACK RATE TO ASSESS ANY RELATIONSHIP WITH SYMPTOMS OCCURRING BETWEEN ATTACKS

Acute hepatic porphyria (HP) often presents with recurrent neurovisceral symptoms in young adults, mimicking more common neurological conditions such as Guillain-Barré Syndrome (GBS) and posing significant diagnostic challenges. We report a case of a 25-year-old male who presented with progressive weakness of all 4 limbs over 4 days, culminating in respiratory paralysis requiring mechanical ventilation. Neurological examination revealed acute flaccid paralysis with areflexia, and nerve conduction studies showed acute motor axonal neuropathy, initially supporting a diagnosis of GBS. However, the patient’s young post-pubertal age, onset in the upper limb with proximal weakness, pure motor axonal neuropathy, and presence of hyponatremia due to the syndrome of inappropriate antidiuresis raised suspicion of acute HP. Screening with qualitative urine porphobilinogen testing, followed by quantitative confirmation, diagnosed acute HP. The patient was treated with intravenous dextrose in the absence of hemin, resulting in gradual clinical improvement. This case underscores the importance of distinguishing acute HP from GBS and the need for early recognition and screening to initiate life-saving therapy.

IntroductionAcute hepatic porphyrias are rare, life-threatening genetic disorders that impair heme biosynthesis, often presenting with nonspecific symptoms that lead to misdiagnosis. This diagnostic challenge and low clinical recognition can delay targeted treatment, increasing morbidity and mortality. Although there have been advances in understanding porphyrias' biochemical pathways, improved diagnostic approaches are still needed, especially in acute care. This study examined diagnostic and clinical patterns of acute hepatic porphyria at a quaternary care hospital in Bogotá, Colombia, to support earlier detection and management.Materials and MethodsThis descriptive, observational, retrospective study reviewed patients diagnosed with acute hepatic porphyria at the Internal Medicine service of a Bogotá hospital from 2013 to 2023. Patients with confirmed diagnoses recorded in the hospital database were included. Data collected covered demographic characteristics, clinical presentation, diagnostic markers, and treatment. Key outcome measures were time to diagnosis, recurrence frequency, and hospitalization duration.ResultsTen patients were included, 80% of whom were female, with a median age of 32 years. Diagnosis was confirmed by urine porphobilinogen tests. All patients reported abdominal pain during attacks; 90% had tachycardia and paresis/weakness of extremities. Attack durations ranged from 4 to 11 days, with 90% treated with hemin. Median hospital stay was 18 days. Drug use and infections were common precipitants, and 40% of female patients had premenstrual-associated attacks.ConclusionsThis study provides a clinical profile of acute hepatic porphyria in a Colombian hospital, highlighting neurovisceral symptoms and female predominance. Findings suggest the need for early diagnostic protocols to prevent treatment delays, although larger studies are required to confirm these findings across different settings.

BackgroundAcute hepatic porphyria (AHP) constitutes a class of rare diseases caused by reduced function in enzymes of the heme-biosynthetic pathway. AHP includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and the extremely rare δ-aminolevulinic-dehydrase deficiency porphyria (ADP). This retrospective study describes characteristics of the Danish AHP patient population.MethodsDepartment of Endocrinology at Odense University Hospital serves as national AHP center. We performed a 5-year retrospective description of our AHP cohort using electronic patient journals. We included general symptoms, number of acute attacks, hospitalization rates, long-term sequelae and symptoms, and grouped patients according to creatinine-adjusted urinary baseline excretion (i.e., outside attacks) of the porphyrin precursor porphobilinogen (PBG) in normal-, moderate- and high-excretion and unknown.ResultsThe cohort contained 129 AHP patients, hereof 100 AIP, 12 HCP and 17 VP. Median age was 46.3 (32.1–62.0) years, and 85 (65.9%) were female. During the 5-years, 38 (29.5%) patients experienced symptoms. Hereof, 20 patients were hospitalized with acute attacks or chronic symptoms and treated with human hemin (n = 14). Most frequently reported symptoms were abdominal pain, nausea, vomiting, and neurological disturbances. Symptoms were more common in patients with high PBG baseline excretion (n = 39) as compared to those with moderate (n = 31) or normal (n = 40) PBG excretion (p = 0.002). Furthermore, females dominated the symptomatic group (68.4%).ConclusionAs reported internationally, AHP is more commonly diagnosed and symptomatic in women, and AIP was the most frequent AHP subtype. Those with an elevated urinary baseline PBG secretion were more likely to report AHP-related symptoms.

RNA therapeutics involves the use of RNA-based molecules to influence biological and molecular processes to treat specific diseases or alleviate symptoms. This includes therapies such as antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA, and aptamers. Fitusiran, an siRNA therapeutic targeting antithrombin, is used for bleeding prevention in hemophilia A and B. RNA interference and splice-switching oligonucleotides are being developed for transfusion-dependent thalassemia with the goal of reducing α-globin synthesis and boosting γ-globin expression. Givosiran, an food and drug administration (FDA)-approved siRNA, treats acute hepatic porphyria. In addition, siRNAs such as Patisiran and Vutrisiran, along with the ASO Inotersen, are FDA-approved for transthyretin amyloidosis. Ongoing research aims to address conditions such as acute myeloid leukemia, myelodysplastic syndromes, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. This review seeks to compile the latest developments in this rapidly advancing area of hematology.

Secondary hypertension and resistant hypertension may result from potentially treatable acquired or hereditary diseases. Inherited Metabolic Disorders are not routinely included in the differential diagnosis of these contexts associated with hypertension, despite the key importance of diagnosis for several of them which enable the early treatment of them. We aim to discuss the current evidence that indicates that a significant portion of cases of unknown resistant hypertension or suspected secondary hypertension may result from unrecognized Acute Hepatic Porphyria (AHP). Diagnostic work-up for AHP is not routinely performed during the evaluation of patients with resistant or refractory hypertension nor in the investigation of secondary hypertension. AHP may present both with neurological and systemic involvement, and hypertension may be observed as part of acute dysautonomia during acute neurovisceral attacks and as a chronic complication during disease course. As AHP represent a potentially treatable group of metabolic disorders, clinicians should consider the inclusion of this group in the diagnostic evaluation of patients with secondary or resistant hypertension.

Acute hepatic porphyrias (AHPs) represent inherited metabolic disorders of the heme biosynthesis pathway, leading to neurological and systemic impairment. Despite the presence of well-recognized chronic symptoms and signs, acute neurological, both neuromuscular and central neurological complications pose a significant challenge in clinical practice, with a potential risk of greater severity and mortality during acute decompensation episodes of AHPs. Care related to the prescription of medications, considering the risk of porphyrinogenicity, is a major and recurring concern in the acute and chronic management of AHP patients. Infectious clinical complications are significant issues in both outpatient and hospital settings for patients with AHPs. It is crucial to identify therapeutic regimens with the best safety and efficacy profiles for treating such infectious complications in AHP patients. The scarcity of structured knowledge available in guidelines and recommendations often leads to the use of therapeutic options with higher potential risks in treating patients with AHPs. This review article aims to provide practical recommendations for managing the most significant infectious complications in clinical practice, with a focus on their impact on the clinical care of patients with AHPs.

RNA interference (RNAi) is a potent biological mechanism enabling the targeted silencing of specific genes, transforming gene regulation and therapeutic approaches in medical science. Using small RNA molecules such as small interfering RNAs (siRNAs) and microRNAs (miRNAs), RNAi allows for precise mRNA degradation or translational repression. Clinically, RNAi has been applied to treat genetic disorders such as hereditary transthyretin amyloidosis (hATTR) and acute hepatic porphyria (AHP). RNAi also holds promise in cancer therapies, targeting oncogenes like KRAS and pathways such as PI3K/AKT/mTOR to slow tumor growth. However, several challenges limit RNAi's broader clinical adoption. A significant barrier is the development of effective delivery systems beyond liver cells, as current methods, such as lipid nanoparticles, have limitations in targeting other tissues. Furthermore, issues such as immune activation, off-target effects, and ensuring RNAi stability must be addressed. Regulatory hurdles concerning long-term safety and gene-silencing specificity also pose challenges. Looking ahead, advancements in next-generation RNAi molecules and delivery platforms, alongside combination therapies, offer promising solutions to overcome these limitations. his review explores the fundamental mechanisms of RNAi, including its role in gene regulation and gene silencing, and highlights its clinical applications in treating genetic disorders, cancers, and viral infections