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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.)

Introduction: porphyria is a rare condition in which heme metabolism is altered., Clinical Case: 29-year-old young man who goes to the emergency room with abdominal pain, vomiting and seizures. To determine the underlying cause, a brain computed tomography (CT) and magnetic resonance imaging (MRI) were performed, confirming the presence of involvement at the parieto-occipital level. Laboratory and urine tests are positive for porphyria, with improvement and resolution of the condition through targeted treatment., Discussion: Porphyrias are rare metabolic disorders with dominant autonomic inheritance that affect heme biosynthesis. In a minority of cases, an external factor can trigger a crisis producing abdominal and neurological symptoms. Imaging findings in acute porphyria are characteristic of PRES (posterior reversible encephalopathy syndrome), with cortico-subcortical involvement., Conclusion: Although it is an uncommon etiology in typical PRES imaging, acute porphyria attacks should be suspected in young patients with seizure attacks without hypertension and associated abdominal pain., (Universidad Nacional de Córdoba)

New treatment options and low attack-related mortality have changed the life expectancy of patients with acute porphyria (AP) to that of the general population. Clinicians should therefore be aware of the long-term complications of AP, which typically include chronic neuropathy and encephalopathy, high blood pressure and porphyria-associated kidney disease. Patients have an increased risk of primary liver cancer (PLC), but no increased risk of non-hepatic cancers. Chronic pain occurs in patients with recurrent attacks, combined with chronic fatigue and nausea, leading to poor quality of life. Patients with sporadic attacks may also have chronic symptoms, which should be distinguished from mild recurrent attacks and treated appropriately. Sequels of acute polyneuropathy after an attack should be distinguished from ongoing chronic polyneuropathy, as the management is different. Overestimation of chronic neuropathy or encephalopathy caused by AP should be avoided, and other causes should be treated accordingly. Prevention of recurrent attacks is the best strategy for managing chronic comorbidities and should be actively accomplished. Hormonal interventions in female patients, or in severe cases, prophylactic givosiran or haematin, may be helpful before liver transplantation to prevent recurrent attacks. Regular monitoring can be personalised according to the patient's age, comorbidities and AP activity. Blood pressure, renal function and cardiovascular risk factors should be monitored annually in patients with previous symptoms. Appropriate medication and lifestyle management, including nutrition and hydration, are necessary to prevent complications. As PLC is common, especially in patients with acute intermittent porphyria, bi-annual surveillance after the age of 50 is important., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

A 17-year-old previously healthy female developed posterior reversible encephalopathy syndrome 1 week after etonogestrel implantation. She had a previous etonogestrel implant removed 4 months prior after unrelenting abdominal pain and hyponatremia with a negative workup for other etiologies, including hypercoagulable disorders and malignancy. This second insertion and resulting hospitalization allowed for the diagnosis of acute intermittent porphyria (AIP) to be confirmed. Progesterone can induce enzymatic activity upstream of porphobilinogen deaminase, the enzyme implicated in AIP, resulting in build-up of toxic metabolites. AIP requires high clinical suspicion for diagnosis but should be considered when hormonal triggers lead to unexplained neurovisceral symptoms., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Healthcare providers evaluating patients presenting with neurological, visceral, or cutaneous symptoms that are disproportionate to the expected severity may need to consider porphyria in the differential. Porphyria is an inherited condition in which toxic metabolites of the heme pathway are increased. Carriers of porphyrias are asymptomatic and will not present with classical symptoms, nor will levels be elevated, until the disease is induced by certain drugs, hormones, or idiopathic causes such as the stress of trauma. Acute intermittent porphyria (AIP), a form of acute porphyria, is a rare autosomal dominant disease that results in a dysfunctional porphobilinogen deaminase. This consequently increases neurotoxic porphobilinogen and subsequent increase in δ-aminolevulinic acid. Both of these metabolites cause neurovisceral symptoms that afflict the patient in acute attacks. We present a rare case of AIP manifested in a burn patient suffering a burn injury. The patient presented with symptoms indicative of AIP, including altered mental status and abdominal pain accompanied with a chronic history of alcoholism and smoking. A negative work-up, including imaging and findings of associated manifestations consistent with AIP led to a discovery of elevated porphyrins. The patient's course and death due to his injuries gives insight into the presentation of AIP in a burn patient., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Acute Intermittent Porphyria (AIP) can be a challenging diagnosis to make, due to its rarity in actual practice and presenting symptoms often being attributed to more common conditions. This is particularly the case, since many patients will likely present to acute and general hospitals where the diagnosis may often not be considered. However, it remains pivotal to diagnose the condition as early as possible to prevent significant morbidity and even death. Here we present an unexpected case of AIP, illustrating the diagnostic delay that is commonly seen with the condition and yet emphasise the importance of its detection to commence urgent treatment.

Rationale: Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting heme production due to enzyme porphobilinogen deaminase deficiency. Diagnosing acute intermittent porphyria is difficult because its symptoms interrelate with those of other common diseases. When AIP is combined with seizures, the diagnosis process is more complicated. This case report shows all tests and criteria used to arrive at the final stage of diagnosis., Patient Concerns: The patient complained of severe abdominal pain, nausea, vomiting, and intermittent convulsions. Her medical history shows she had abdominal pain, mainly dull pain in the left upper abdomen., Diagnoses: Different symptomatic tests were done, and the cause of her symptoms was uncertain. A urine sun drying test was then done and confirmed the presence of porphyrin used to diagnose AIP. A genetic test was done after the patient was discharged, and AIP diagnosis was confirmed., Interventions: Acute intermittent porphyria treatment was administered., Outcomes: The patent recovered fully., Lessons: It is essential to consider acute intermittent porphyria diagnosis in patients having unexplained severe abdominal pain associated with neurological and psychiatric symptoms. Since AIP is a rare disease with a high mortality rate when not treated early, Clinical practices should include AIP as one of the tests done on patients showing these symptoms at an early stage. The fastest way to identify this is to conduct a urine test. The change of color from brown to reddish color is a diagnostic indicator of AIP. This strategy helps reduce misdiagnoses and delayed treatment of the right disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is no definitive guidance on whether patients with acute intermittent porphyria (AIP) with recurrent attacks need pharmacological prophylactic treatment., Methods: The management strategies for patients with frequent (defined as ≥4 annualized attack rate (AAR) and less frequent attacks (<4 AAR), including treatment for acute attacks and duration of prophylaxis (weekly heme arginate 3 mg/kg body weight and/or investigational drug, givosiran), were summarized. The AAR for the following periods were presented: the first 2 years after diagnosis, before/after prophylaxis, and the most recent 2 years., Results: A total of 29 patients with AIP were included, 19 (34.5%) had <4 AAR and 10 (65.6%) had ≥4 AAR in the first 2 years after diagnosis. All patients experienced reduced attacks during the treatment course, 23 (79.3%) were attack-free during the most recent 2 years. Among the 9 patients who received prophylaxis (7 heme arginate; 1 givosiran, 1 heme arginate followed by givosiran), 5 (55.6%) were attack-free in the most recent 2-year period and prophylaxis was discontinued because there had been no attacks for >1 year. For patients without prophylaxis (n = 20), 18 (90.0%) were attack-free in the most recent 2-year period and 15 (75.0%) experienced attacks only in the first 2 years after diagnosis., Conclusions: Prophylaxis could be considered for patients with AIP with ≥4 biochemically confirmed attacks/year after routine treatment of 1-2 years, during which the severity and frequency of attacks should be closely monitored to determine the necessity of pharmacologic prophylaxis. More studies are needed to reach a consensus on the use of pharmacological prophylaxis and treatment of AIP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Rationale: Acute intermittent porphyria (AIP) is a rare genetic disorder that affects porphyrin metabolism in the blood. The disease causes defects in specific enzymes in the body, which in turn leads to the accumulation of porphyrin metabolites. Patients may experience abdominal pain, neurological symptoms, muscle pain, and nausea, but it does not directly cause pancreatitis., Patient Concerns: The patient is a young woman, 23 years old, who was admitted to our hospital with intermittent abdominal pain for 2 days, the pain was not fixed, episodic, with no obvious trigger, and 1 day before admission, the patient started to experience nausea and vomiting, with gastric contents as the vomitus, and similar symptoms had occurred many times in the past. Blood amylase 600 U/L, blood sodium 120.6 mmol/L, blood routine, and coagulation function results were normal; abdominal CT showed pancreatic swelling with unclear surrounding fat interstitial, acute pancreatitis was considered. The patient's urine was dark red, and the results of the qualitative urine porphyrin test were positive., Diagnoses: AIP complicated with acute pancreatitis., Intervention: Relief of symptoms, control of pain, correction of electrolyte disturbances, and high-carbohydrate therapy., Outcomes: The patient was discharged with complete symptomatic relief after 10 days of high-carbohydrate therapy., Lessons: AIP complicated with acute pancreatitis is very rare. Treatment of AIPs aims to control acute attacks and prevent potential triggers., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Acute porphyrias are a group of rare genetic metabolic disorders, caused by a defect in one of the enzymes involved in the heme biosynthesis, which results in an abnormally high accumulation of toxic intermediates. Acute porphyrias are characterized by potentially life-threatening attacks and, for some patients, by chronic manifestations that negatively impact daily functioning and quality of life. Clinical manifestations include a nonspecific set of gastrointestinal, neuropsychiatric, and/or cutaneous symptoms. Effective diagnostic methods are widely available, but due to their clinical heterogeneity and non-specificity, many years often elapse from symptom onset to diagnosis of acute porphyrias, delaying the treatment and increasing morbidity. Therefore, increased awareness of acute porphyrias among healthcare professionals is paramount to reducing disease burden. Treatment of acute porphyrias is centered on eliminating the potential precipitants, symptomatic treatment, and suppressing the hepatic heme pathway, through the administration of hemin or givosiran. Moreover, properly monitoring patients with acute porphyrias and their relatives is fundamental to preventing acute attacks, hospitalization, and long-term complications. Considering this, a multidisciplinary panel elaborated a consensus paper, aiming to provide guidance for an efficient and timely diagnosis of acute porphyrias, and evidence-based recommendations for treating and monitoring patients and their families in Portugal. To this end, all authors exhaustively reviewed and discussed the current scientific evidence on acute porphyrias available in the literature, between November 2022 and May 2023.

Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ∼⅓ of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as "variants of uncertain significance" (VUSs). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino acid substitutions. The resulting variant effect maps generally agreed with biochemical expectations and provide further evidence that HMBS can function as a monomer. Additionally, the maps implicated specific residues as having roles in active site dynamics, which was further supported by molecular dynamics simulations. Most importantly, these maps can help discriminate pathogenic from benign HMBS variants, proactively providing evidence even for yet-to-be-observed clinical missense variants., Competing Interests: Declaration of interests F.P.R. is an investor in Ranomics, Inc., and is an investor in and advisor for SeqWell, Inc., BioSymetrics, Inc., and Constantiam Biosciences, Inc., and has accepted conference travel support from Illumina, Inc. L.F., A.C., and R.N. are employed by and invested in Invitae. R.J.D. has received both a grant and royalties and has also served as a consultant for Alnylam Pharmaceuticals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Acute intermittent porphyria (AIP) is caused by a partial deficiency of hydroxymethylbilane synthase and affects heme biosynthesis. Mutations in the HMBS gene result in HMBS deficiency. AIP is a rare disease, and there been insufficient studies on it. This report describes the molecular epidemiology of HMBS gene defects and hydroxymethylbilane synthase activity levels in classical AIP., Methods: Databases of PubMed, CNKI, and Wang Fang Database were searched for eligible studies to investigate HMBS gene mutations in peripheral blood samples and HMBS activity in erythrocytes of patients with classical AIP. Relevant studies published up to July 15, 2023, from several databases were independently searched and selected by 2 reviewers. Accuracy data and relevant information were extracted from each eligible study by 2 independent researchers and analyzed using statistical software., Results: After pooling the accuracy data from 232 patients of the 15 eligible studies, 90.5% (210/232) of AIP patients had decreased erythrocyte hydroxymethylbilane synthase activity (<70%), and 96 different mutations were identified in 232 patients, including 33 missense (34.4%), 27 splice (28.1%), 19 deletion (19.8%), 8 nonsense (8.3%), 9 insertion (9.4%) mutations. Residual enzyme activities (%) for different groups of type were expressed using mean and 95% confidence interval (95% CI): missense (51.2, 48.5-53.9), splice (57.5, 52.0-59.1), deletion (54.9, 50.7-59.1), nonsense (52.2, 44.4-60.0), insertion (53.2, 47.4-59.0), group analysis P = .17. Subgroups of missense mutations, domain 1 (50.2, 46.0-54.4), domain 2 (52.8, 49.1-56.4), and domain 3 (49.2, 38.3-60.0), Subgroup analysis, P = .62., Conclusion: Different mutation types and mutation positions are not associated with the level of hydroxymethylbilane synthase activity. Erythrocyte hydroxymethylbilane synthase activity is often reduced to half of normal in patients with AIP, and the enzyme activity assay has a high diagnostic value in AIP. AIP is highly molecularly heterogeneous, with missense mutations being the most common, followed by splice mutations. R173W and G111R are high-frequency mutations and have been found in multiple families from different countries., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.

Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias., Competing Interests: None

Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by two Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. A total of 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of nine terms and definitions. A total of 34 experts were invited to take part in the Delphi rounds. Seven of the initial nine terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all nine definitions achieved agreement. Agreement on the definitions for nine important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence-based clinical guidelines., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

A 31-year-old female presented to the emergency department with abdominal pain, vomiting and constipation. Serum sodium levels were recorded at 110 mmol/L on admission, dropping to 96 mmol/L despite fluid restriction. The patient developed hallucinations and required hypertonic saline administration in critical care. Urinary sodium was detected at 149 mmol/L, consistent with syndrome of inappropriate antidiuretic hormone secretion (SiADH). Urinary porphyrins were also raised, consistent with a diagnosis of acute intermittent porphyria with SiADH as a complication.

Background: Acute intermittent porphyria (AIP) is an uncommon metabolic disease, being the most common of the acute porphyrias. The most frequent symptom is acute abdominal pain, although can be accompanied by seizures, neuro-psychiatric alterations or symmetrical motor neuropathies, which in some patients can progress to respiratory musculature paralysis., Objective: To describe an atypical presentation of acute porphyria to be considered as differential diagnoses in abdominal pain., Clinical Case: We present a case of a patient with AIP, presenting acute abdomen, seizures, later developed neuropsychiatric compromise and symmetrical motor neuropathy, and was admitted to mechanical ventilation. Due to the severity of the neurological involvement, he received hemin arginate, presenting with transient hypertransaminemia, an adverse event not previously reported. The evolution was favorable, with mechanical ventilation and hospital discharge withdrawn., Conclusions: The diagnosis of AIP should be considered in cases of acute abdominal pain associated with neurological and/or psychiatric symptoms, particularly young women. The administration of hemin is considered the standard of treatment, and even late could have beneficial effects., (© 2023 Revista Médica del Instituto Mexicano del Seguro Social.)

Porphyrias, particularly acute intermittent porphyria (AIP), are rare, inherited disorders of heme synthesis. On the other hand, systemic lupus erythematosus (SLE) is an uncommon autoimmune disease that affects women predominantly. The coexistence of AIP and SLE is rare. We report a case of concomitant diagnosis of AIP and SLE in a 21-year-old woman who presented with recurrent acute abdominal, chest, and back pain associated with nausea and vomiting, followed by arthralgia, multiple joint pain, and rash. Investigations revealed severe hyponatremia related to SIADH (syndrome of inappropriate antidiuretic hormone secretion) with a positive SLE antibody panel and a positive urine screen for porphobilinogen. Molecular test confirmed the diagnosis of AIP with a pathogenic mutation in the HMBS gene.

Background: Prompt diagnosis of metabolic disorders in a resource-limited country like Nepal is daunting. Acute intermittent porphyria is a rare but common hepatic porphyria mostly seen in females of the reproductive age group. As its incidence is quite uncommon, conjectures about porphyria diagnosis are often duped into a diagnostic conundrum., Case Presentation: Here we unravel a case of a 15-year-old Hindu Nepalese girl distraught by the myriad of symptoms in the setting of severe abdominal pain accompanied by constipation and limb pain as the chief complaints. She presented with acute severe hypertension with marked persistent hyponatremia (up to 109 mEq/L). Despite conservative management of hypertension and electrolytes, unresolved electrolyte imbalance led us to the speculation of disturbance in the renin-angiotensin-aldosterone system. Due to her exacerbating neurovisceral status, she also required intensive care during the disease course. After thorough investigations and exemption of presumed provisional diagnoses, based on sustained symptomatic presentation, the clinical suspicion was driven towards a diagnosis of porphyria-related disorders. Positive Watson-Schwartz test substantiated the diagnosis of acute intermittent porphyria. Her symptoms gradually abated after the consumption of high carbohydrate diets., Conclusion: This case highlights the baffling amalgamation of symptoms that simulate common diseases of concern yet are buried in the realm of porphyric disorders. Porphyria can be diagnosed using simple screening tools and timely treatment can diminish serious consequences., (© 2022. The Author(s).)

BACKGROUND Acute intermittent porphyria (AIP) is a rare genetic disease caused by the deficiency of porphobilinogen deaminase enzyme in the heme synthesis pathway. AIP is passed by autosomal dominant inheritance. Heterozygous pathogenic variants in hydroxymethylbilane synthase (HMBS) are associated with AIP. Multisystemic manifestations of acute neurovisceral features exist, which are quite challenging for diagnosis. Currently, few patients worldwide have been reported with AIP. A small number of reports have been published in Thailand, but none have been confirmed by molecular genetics diagnosis. CASE REPORT A 14-year-old female adolescent presented with severe intermittent abdominal pain, vomiting, seizure, posterior reversible encephalopathy syndrome, syndrome of inappropriate antidiuretic hormone, and muscle weakness, which are all classic phenotypes of an acute AIP attack. The patient received several investigations before AIP was suspected. High levels of urine porphobilinogen, high levels of urine aminolevulinic acid, and a heterozygous known pathogenic variant in HMBS: c.517C>T (p.Arg173Trp) were identified. Therefore, AIP was the definitive diagnosis. Then, Sanger sequencing testing was performed for the patient's family; this variant was found in her father, paternal grandmother, and sister, who were all asymptomatic (latent AIP). After the AIP was confirmed, high carbohydrate loading was given as a standard treatment. She had a full recovery; her clinical course of the attack episode lasted for 8 weeks. CONCLUSIONS An early diagnosis of AIP leads to prompt and specific treatment, which can shorten the duration of attacks, prevent complications, reduce the cost of treatment, and reduce the mortality rate.

Porphyrias are disorders of the haem biosynthesis which are encountered infrequently and which often present themselves atypically as a combination of gastrointestinal, neurologic and/or dermatologic symptoms. Although they are primarily caused by enzyme defects, inheritance patterns are mostly not evident. Considering all of these characteristics, it is not surprising that there is a long delay between the onset of symptoms and the diagnosis of the disease, with as possible consequences impaired quality of life, irreversible neurologic damage and even death. This review aims to increase the clinical suspicion of the three most common porphyrias in adults: acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT) and protoporphyria. Their relevant pathophysiology, clinical manifestations, diagnosis and treatment are discussed aiming at increasing the awareness of these diseases among physicians.

A 40-year-old man attended the emergency room with abdominal pain and inappropriate behaviour associated with stress, and the consumption of alcohol and cannabis. Examination revealed hypertension (155/100 mmHg), tachycardia (95 beats per minute), abdominal pain and leucocytosis with neutrophilia, hyponatraemia and hypokalaemia. Urine was positive for nitrites, elevated bilirubin and cannabinoids. The patient was diagnosed with acute intermittent porphyria (AIP) and immediately treated. After initial treatment, the patient improved. However, he subsequently relapsed after initiating treatment with oseltamivir for a flu-like illness. Treatment was discontinued and the patient progressed favourably. AIP recurrence could have been mediated by oseltamivir; an association not previously described in the literature., (© Royal College of Physicians 2022. All rights reserved.)

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., (© 2022. The Author(s).)

Porphyrias are a group of rare, mostly inherited metabolic disorders of heme biosynthesis. Each type of porphyria results from a specific deficiency of one of the pathway enzymes, causing a characteristic accumulation and excretion of heme precursors. Diagnosis is confirmed by the biochemical detection of these porphyrins and the precursors in urine, feces and blood. Porphyrias can be classified into acute and non-acute forms. The clinical presentation is unspecific and includes acute neurovisceral and/or cutaneous symptoms. The latent phase can evolve into a potentially life-threatening acute crisis, which is often misdiagnosed. The four acute hepatic porphyrias are relevant for anesthesiologists as precipitating factors are commonly found in the perioperative setting. Safe anesthetic management in cases of known porphyria is possible by adherence to current recommendations. The immediate administration of heme arginate as specific treatment for acute attacks is decisive for the outcome., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The acute porphyrias are a group of four metabolic defects in which the heme synthesis in the liver is disrupted. They are characterized by massively painful acute attacks, which can be life-threatening if not diagnosed. To raise the awareness for these rare disorders, a heme molecule in cartoon style is introduced, which accurately explains the basic biochemical processes in the body and mediates important information on the acute hepatic porphyrias in a simplified and attractive way. The article is complemented by a case report., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Acute intermittent porphyria (AIP) is a rare autosomal dominant inherited disease, predominantly seen in female patients, caused by mutations in the hydroxymethylbilane synthase gene. When impaired, elevated heme biosynthesis precursor levels accumulate in the liver, resulting in neurological symptoms, psychiatric disturbances, darkened urine color, abdominal pain, nausea, vomiting, and ileus. We present a 22-year-old Hispanic female with diffuse abdominal pain and no bowel movements for 8 days. She reported recent antibiotic and oral contraceptive pill use. Computerized tomography of her abdomen revealed a dilated small bowel and marked colonic distension. A colonoscopy found mild nonspecific inflammation in the rectosigmoid and terminal ileum. Her abdominal pain persisted despite interventions and improvements in appetite, bowel movements, abdominal imaging, and treatment of an identified Clostridium difficile infection. A random urine porphobilinogen was then obtained and found to be elevated. Fractionation of plasma and urine porphyrins was suggestive of AIP. Her symptoms improved with 3 days of intravenous (IV) hematin and IV dextrose. This is a unique case of a rare disease due to her clinical presentation with ileus, unremarkable past medical history, family history, and the prehospitalization and intrahospitalization factors that likely exacerbated the patient AIP.

A partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (HMBS) leads to acute intermittent porphyria (AIP), a severe neurovisceral, autosomal dominant disorder with low penetrance. Even though in-depth investigations of the HMBS variants have been carried out by researchers in Britain, France, Russia, and Sweden, this area remains uninvestigated in China owing to the rarity and lack of clinical understanding of the disease. In this study, 78 unrelated AIP patients revealed 48 different HMBS variants, of which 17 were novel. These included 22 missense variants, 9 splicings, 5 nonsense variants, 10 small deletions, 1 repeat insertion, and 1 complex deletion-insertion variant. The variant c.673C > T, found in 10 unrelated patients, was the most frequent variant, followed by the variant c.517C > T, found in 7 unrelated patients. We performed western blotting and immunofluorescence staining with four novel variants (c.653G > A, c.597dupC, c.726-727del, and c.1045&#95;1046delAA) to detect the expression levels of mutant HMBSs. The results showed a variant-mediated decrease in the mutant-HMBS level, suggesting that the variant resulted in impaired gene product functions. Moreover, the in vitro functional verification in this study provided PS3&#95;moderate evidence for American College of Medical Genetics and Genomics (ACMG) to grade the pathogenicity of novel variants in AIP., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and their chameleon-like presentation, delayed diagnosis and misdiagnosis are common. AHPs are genetically inherited disorders that result from heme biosynthesis enzyme deficiencies and comprise four forms: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA-dehydratase porphyria (ALADP). Depending on the clinical presentation, the main differential diagnoses are Guillain-Barré syndrome and autoimmune encephalitis. Red flags that could raise the suspicion of acute porphyria are neurological symptoms starting after severe (abdominal) pain, in association with reddish urine, hyponatremia or photodermatitis, and the presence of encephalopathy and/or axonal neuropathy. We highlight the diagnostic difficulties by presenting three cases from our neurological intensive care unit and give a comprehensive overview about the diagnostic findings in imaging, electrophysiology, and neuropathology., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Abdominal pain is a common reason for emergency department visits, with many patients not receiving a definitive diagnosis for their symptoms. Non-gastrointestinal causes need to be considered in the workup of abdominal pain. A high index of suspicion is needed in order to develop a broad differential, and a thorough history and physical examination is paramount. This article will discuss some of these diagnoses, including can't miss diagnoses, common non-abdominal causes, and rare etiologies of abdominal pain., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute intermittent porphyria (AIP) is an autosomal dominant genetic disease caused by a lack or decrease in hydroxymethylbilane synthase (HMBS) activity. It is characterized by acute nerve and visceral attacks caused by factors in the process of heme synthesis. The penetrance rate of this disease is low, and the heterogeneity is strong. Here, we reported two novel HMBS mutations from two unrelated Chinese AIP patients and confirmed the pathogenicity of these two mutations. We found the HMBS c.760-771+2delCTGAGGCACCTGGTinsGCTGCATCGCTGAA and HMBS c.88-1G>C mutations by second-generation sequencing and Sanger sequencing. The in vitro expression analysis showed that these mutations caused abnormal HMBS mRNA splicing and premature termination or partial missing of HMBS protein. Homologous modeling analysis showed that the HMBS mutants lacked the amino acids which are crucial for the enzyme activity or the protein stability. Consistently, enzyme activity analysis confirmed that the HMBS mutants' overexpression cells exhibited the reduced enzyme activity compared with the HMBS wildtype overexpression cells. Our study identified and confirmed two novel pathogenic HMBS mutations which will expand the molecular heterogeneity of AIP and provide further scientific basis for the clinical diagnosis of AIP.

Porphyrias are a set of rare inherited metabolic disorders, each of them representing a defect in one of the eight enzymes in the haem biosynthetic pathway resulting in the accumulation of organic compounds called porphyrins. Acute hepatic porphyrias (AHP) are those in which the enzyme deficiency occurs in the liver, of which acute intermittent porphyria is by far the most common subtype. Neurology of the AHP is still challenging in practice, and patients rarely receive the correct diagnosis early in the disease course. For AHP, which primarily affects the central and peripheral nervous system, the cause of symptoms seems to be the increased production of neurotoxic precursors, in particular delta-aminolaevulinic acid and porphobilinogen. Neurological complications usually result from severe episodes of acute attacks. The neurologic hallmark of porphyrias is an acute predominantly motor axonal neuropathy resembling a Guillain-Barré syndrome that generally occurs after the onset of other clinical features such as abdominal pain and central nervous system manifestations. Neuropsychiatric syndromes, seizures, encephalopathy, and cerebrovascular disorders are among the possible central nervous system presentations. Therapeutic approach to AHP is divided into management and prophylaxis of an acute attack, including long standing options such as intravenous hematin and new therapeutic agents such as givosiran., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.