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Diagnosis Algorithm for Acute Neurovisceral Symptoms Leading to Suspicion of Porphyria. * Biochemical markers also detected in the latent phase. ADP, aminolevulinic acid dehydratase porphyria; AIP, acute intermittent porphyria; ALA, aminolevulinic acid; HCP, hereditary coproporphyria; HMBS, hydroxymethylbilane synthase; PBG, porphobilinogen; VP, variegate porphyria.
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The porphyrias are a group of rare metabolic disorders, inherited or acquired, along the heme biosynthetic pathway, which could manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Neurovisceral porphyrias are characterized by acute attacks, in which excessive heme production is induced following exposure to a t...
Context in source publication
Similar publications
The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5‐aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed...
Citations
... Patients with AIP can retain up to 50% of enzyme activity when the mutated HMBS gene is inherited from one of their parents, a level sufficient for normal hemoglobin synthesis. As a result, most patients are asymptomatic carriers (12). AIP has been reported worldwide, with its distribution varying across regions and populations. ...
Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder resulting from increased production of porphyrins and their precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), due to deficiencies in the enzymatic activity of the heme synthesis pathway. The disease is typically characterized by a triad of abdominal pain, neurologic impairment symptoms, and psychiatric abnormalities. However, only a small percentage of patients present with this classic triad of symptoms. Our female patient, aged 23, was admitted to the hospital with a 4-year history of abnormal mood episodes and weakness in the limbs for over 1 week. She had a previous medical history of intestinal obstruction. After admission, a cranial MRI revealed reversible posterior leukoencephalopathy imaging manifestations, and the patient exhibited weakness of the extremities, respiratory failure, seizures, and severely reduced serum sodium concentration. The diagnosis of AIP was ultimately confirmed by a positive urine PBG-sunlight test and analysis of HMBS gene variants. The absence of typical triadic signs in acute attacks of AIP can make early recognition of the disease challenging. We present a case with multiple typical clinical manifestations of AIP in the hope of aiding clinicians in fully recognizing acute intermittent porphyria.
... 1,2 Each type of porphyria derives from a specific deficiency in one of the enzymes involved in the pathway and, accordingly, is characterized by a specific pattern of accumulation of heme precursors and typical clinical manifestations. 3 Four types of porphyrias constitute the group of acute hepatic porphyrias (AHP): 5-aminolevulinic acid (5-ALA) dehydratase deficiency porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HP), and variegate porphyria (VP). Acute hepatic porphyrias are characterized by acute attacks 4 in which excessive heme is produced following an exposure to a trigger. ...
Objective:
In patients with acute hepatic porphyria (AHP), prolonged fasting is a known trigger of AHP attacks. Despite this, some Jewish AHP patients-mainly hereditary coproporphyria (HCP) and variegate porphyria (VP) patients-fast for 25 consecutive hours during the traditional Jewish holy day known as Yom Kippur. In this study, we evaluated the effect of the fast on these patients.
Methods:
A retrospective study and survey of AHP patients in Israel was carried out. Patients were asked whether they have fasted and whether any symptoms were induced by this fast. Patients' medical records were reviewed for an emergency department (ED) visit following Yom Kippur between 2007 and 2019. Only 3 acute intermittent porphyria (AIP) patients reported fasting; they were excluded from analysis.
Results:
A total of 21 HCP patients and 40 VP patients completed the survey; 30 quiescent patients reported they fast, while 31 did not fast. The majority of fasting patients (96.67%) reported no symptoms following a fast. We found no statistically significant association between ED visits 1 week (0.26% in both fasting and non-fasting patients) or 1 month (2.1% visits in non-fasting versus 0.78% in fasting patients) following Yom Kippur. Of the symptomatic ED visits following a fast, none were defined as severe attacks.
Conclusion:
A 25-hour fast in stable HCP and VP patients did not increase the risk of an acute attack and can probably be regarded as safe.
... Porphyrias are rare metabolic disorders, which comprise a group of inherited and acquired disorders wherein there is a partial or complete deficiency of enzymes in the heme biosynthetic pathway [1]. Disturbance in the heme synthetic pathway causes the intermediates in these steps to accumulate. ...
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.
... The porphyrias are a group of rare metabolic disorderseither inherited or acquired, which affect the heme biosynthetic pathway [1,2]. ...
Introduction
Several abnormalities of porphyrin metabolism leading to Porphyria Cutanea Tarda (PCT) have been described in early studies of End Stage Renal Disease (ESRD) patients, with a reported prevalence of 5–18%. We aimed to evaluate porphyrin levels and correlation to skin manifestations in modern dialysis era.
Methods
The study cohort included adult hemodialysis patients from a single center tertiary medical center. All patients underwent a full skin examination, completed the Dermatology Life Quality Index questioner, and provided a blood sample for porphyrin levels assessment.
Results
A total of 94 adult hemodialysis patients were recruited to the study. No clinical PCT was diagnosed. Porphyrin levels did not correlate with any clinical or dialysis quality parameters.
Conclusions
In modern hemodialysis era, possibly due to improved porphyrins' metabolism and dialysis removal, PCT is much less prevalent among hemodialysis patients than previously reported in the past.
... Las porfirias comprenden un grupo de ocho trastornos, cada uno de ellos representa un defecto en uno de los ocho pasos de la formación del hemo, que se da por una mutación en el gen que codifica para cada enzima de la vía; de acuerdo con esto, se presenta una acumulación de porfirinas las cuales entran a la circulación y son excretadas en la orina o heces. Las manifestaciones clínicas se producen de acuerdo con la enzima deficiente y tipo de porfiria 1,2 . Durante el siglo XIX se observó que en los pacientes que se describieron con esta alteración la orina era de color rojiza, debido al exceso de porfirinas, y cuando se exponía a la luz se oscurecía mucho más, por lo que se le dio el nombre de porfiria, término derivado de la palabra griega porphyrus que significa púrpura 3 . ...
... Universidad Técnica de Manabí. Portoviejo, Ecuador citocromos respiratorios, citocromo P450 (CYP450), los cuales participan en la inactivación y eliminación de muchas drogas 16 , de catalasas, peroxidasas, triptófano pirrolasa y óxido nítrico sintetasa, los cuales tienen un papel importante en el transporte de oxígeno y los procesos de óxido reducción 1,3,17,18 . ...
... Las porfirias, como se explicó al principio, comprenden un grupo de ocho trastornos; cada uno de ellos representa un defecto en uno de los ocho pasos de la formación del hemo, que se da por una mutación en el gen que codifica para cada enzima de la vía 1 (Figura 3). Para su mejor comprensión las porfirias se han subdividido en formas hepáticas y eritropoyéticas, de acuerdo con el sitio de expresión de la enzima disfuncional; sin embargo, en un contexto clínico es más conveniente clasificarlas de acuerdo con sus manifestaciones clínicas en hepáticas agudas (neuroviscerales), crónicas cutáneas (lesiones en piel por fotosensibilidad) y mixtas (agudas + cutáneas) 1 4. Clasificación de las porfirias según las características de sus síntomas en agudas neuroviscerales y crónicas cutáneas; y la clasificación según el lugar de expresión de la enzima disfuncional: en hepáticas, eritropoyéticas y hepatoeritropoyéticas. Tomada y modificada de Layer et al. 20 . ...
Las porfirias comprenden un grupo de ocho tipos diferentes de desórdenes genéticos en la vía de la síntesis del grupo hemo, con la característica de que sus manifestaciones clínicas pueden confundirse con las de otras patologías médicas. Para la mayoría de los médicos generales y especialistas la porfiria representa un grupo de enfermedades que no se diagnostican frecuentemente, por lo que se catalogan como raras, y no se les da el reconocimiento adecuado; muchas veces sus síntomas se ignoran o malinterpretan, lo que lleva a un retardo en el diagnóstico y el tratamiento. Las porfirias se han subdividido de acuerdo con sus manifestaciones clínicas en agudas (neuroviscerales) y crónicas (cutáneas). El diagnóstico se puede confirmar rápidamente demostrando niveles marcadamente elevados de porfobilinógeno, de ácido 5-aminolevulínico en orina e isómeros de porfirinas en sangre y orina. La terapia con hemina intravenosa se debe iniciar rápidamente, si hay sospecha clínica y si se encuentra el porfobilinógeno elevado en orina, ya que el ácido 5-aminolevulínico es menos específico y puede estar elevado en pacientes con intoxicación por plomo o tirosinemia hereditaria tipo I. Las porfirias son un grupo de enfermedades subdiagnosticadas que pudieran considerarse al momento de estudiar pacientes con orina coloreada en conjunto con manifestaciones cutáneas y/o neuroviscerales.
... The significant increase of nalbuphine indicates that the immune response was activated in the OA-exposed rats (Inan et al. 2019;Yu et al. 2019). Coproporphyrin I and III are regarded as markers of Porphyria whose clinical symptoms include abdominal pain, vomiting, nausea, paralysis, and respiratory failure, etc. Edel and Mamet 2018;Wang et al. 2019). The significant increase of coproporphyrin I and III in the OA-exposed rats may give some explanation for the abdominal pain, vomiting, and nausea caused by OA, and In addition, several amino acids, peptides, and analogues (such as N-Acetyl-leu-leu-tyr, Lysyl-Arginine, l-Aspartic Acid, Aspartyl-Proline, and l-Glutamate, etc.) were highly correlated with the content of OA and might be involved in the metabolism of OA, though we failed to find the kernel ( Table 1). ...
Okadaic acid (OA) is an important marine lipophilic phycotoxin with various pathological properties, responsible for diarrheal shellfish poisoning events in human beings over the world. However, to date no mechanism can well explain the toxicity and symptom of OA, even diarrhea. Here, to reveal the toxic mechanism of OA to mammals, we analyzed the metabolism of OA in rat and the effects of OA exposure on the composition and function of gut bacteria using a multi-omics strategy and rRNA high-throughput technology. We found that OA exerted great effects on gut bacteria, mainly featured in heavy fluctuation of dominant genera and significant changes in the mapped bacterial function genes, including not only virulence genes of pathogenic bacteria, but also bacterial metabolism genes. In the feces of the OA-exposed group, we detected dinophysistoxin-2 (DTX-2), lespedezaflavanone F and tolytoxin, suggesting that OA could be transformed into other metabolites like DTX-2. Other metabolic biomarkers such as N-Acetyl-a-neuraminic acid, N,N-dihydroxy-l-tyrosine, nalbuphine, and coproporphyrin I and III were also highly correlated with OA content, which made the toxicity of OA more complicated and confusing. Spearman correlation test demonstrated that Bacteroides and Romboutsia were the genera most related to OA transformation, suggesting that Bacteroides and Romboutsia might play a key role in the complicated and confusing toxicity of OA. In this study, we found for the first time that OA may be converted into other metabolites in gut, especially DTX-2. This finding could not only help to reveal the complex toxicity of OA, but also have important significance for clarifying the transportation, metabolism, and environmental fate of OA in the food chain.
... Sensory loss can also occur but objective loss is rare. Mental disturbances (caused by the raised PBG and ALA) include anxiety, disorientation or hallucinations, and psychosis rarely [1,9]. ...
... The most frequent presenting signs in patients with AIP are tachycardia, dark urine, confusion, peripheral motor deficit, low or absent deep tendon reflex, cranial neuropathy, and sensory loss. Oxidation of PBG to uroporphyrin and porphobilin causes purple discoloration of urine [9]. The white blood cell count may be elevated because of stress or infection. ...
... In our patient, the diagnosis of AIP was based on clinical and urinary findings. Early diagnosis is essential to avoid progression of attacks to severe neurological complications such as motor paralysis and to institute early effective therapy [1,9]. ...
Acute intermittent porphyria (AIP) is a rare autosomal dominant and the most severe form of the inherited hepatic porphyrias, affecting mainly young women. We present the case of an 18-year-old female who presented with severe abdominal pain, purple urine, autonomic dysfunction, and severe hyponatremia, seizures on further evaluation came out to be a case of AIP. This case report is a reminder to keep AIP among the differentials in young female patients with a classic constellation of abdominal urine discoloration syndrome of inappropriate secretion of antidiuretic hormone and autonomic dysfunction.
... Acute attacks of AHP are predominantly (80%-90% of the cases) seen in women of reproductive age group. 1 AHP does not manifest with cutaneous symptoms such as skin bullous lesions, pushing the suspicion of porphyria further away. 2 Intriguingly in AHP, symptoms of the disease in the same patient during different episodes and in different patients with the same porphyria subtype are different. 3 Our patient, a young woman, presented with nonspecific abdominal pain and generalised weakness in limbs. ...
Variable, non-specific presentation makes acute hepatic porphyria a diagnostic challenge, warranting a good clinical acumen. Clinical cues like urine turning dark on standing are overlooked due to inadequate patient-interaction, thus underscoring the importance of a dedicated bed-side workup. Simple method like urine examination under ultraviolet light should be used to accelerate the diagnosis, particularly in peripheral healthcare settings where timely urine porphyrin estimation is not feasible.
... 11 The pathophysiology of hyponatraemia in acute porphyria, despite being frequently reported in as many as 40% of cases, is still not very well understood. 12 While it has been attributed in some reports to the syndrome of inappropriate antidiuresis, there may also be elements of renal or gastrointestinal sodium loss. 13 Despite the number of patients with tyrosinaemia known worldwide and the likelihood of the existence of non-adherent older patients with complications and morbidities, to the best of the authors' knowledge, SIADH has not been reported among patients with tyrosinaemia type 1. ...
Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a recognisable complication of acute porphyria. We report a nine-year-old female patient with hereditary tyrosinaemia type 1 and poor adherence to nitisinone therapy who presented with acute abdominal pain, vomiting and lethargy at Sultan Qaboos University Hospital, Muscat, Oman in 2016. She subsequently developed generalised tonic-clonic seizures attributable to severe hyponatremia that met the diagnostic criteria of SIADH. The acute porphyria screen also appeared positive. The patient responded well to fluid restriction and was discharged home without immediate neurological sequelae. Although acute porphyria is also a recognised complication of uncontrolled tyrosinaemia type 1, to the best of the authors’ knowledge, no patient with tyrosinaemia type 1 has been reported to present with SIADH. Keywords: Tyrosinemia Type 1; Hyponatremia; Inappropriate ADH Syndrome; Case Report; Oman.
... The porphyrias are a group of rare metabolic disorders, either inherited or acquired, caused by a specific abnormality in one of eight enzymes of the heme biosynthetic pathway [1,2]. They may be subdivided by the predominant site of the enzyme defect, into hepatic and erythropoietic forms, or by their clinical manifestations, into acute (neurovisceral) and non-acute (cutaneous) forms [3][4][5]. Variegate porphyria (VP) and hereditary coproporphyria (HCP) are referred to as mixed or neurocutaneous porphyrias (NCPs) because patients can have both potentially life-threatening acute neurovisceral symptoms and cutaneous symptoms. Both are inherited in an autosomal dominant mode with low penetrance [6,7]. ...
... Both are inherited in an autosomal dominant mode with low penetrance [6,7]. Acute porphyric attacks are characterized by pain, usually abdominal, often accompanied by sympathetic overactivity (systemic arterial hypertension, tachycardia, sweating) and other neurological manifestations (severe fatigue, anxiety, confusion and seizures) [2,5,8,9]. Most of the current information on the clinical systemic manifestations of acute porphyrias is derived from studies of acute intermittent porphyria (AIP) which is more common than HCP and VP [8,[10][11][12][13], while data on NCPs are relatively limited [8,14,15]. ...
... Coupled systemic and cutaneous presentation was also more prevalent in the VP group (40% vs. 5%, p = Table 4 outlines specific aggravating factors reported by patients with NCP sys . Most are known to promote the activity of 5-aminolevulinate synthase 1 (ALAS1) via induction of cytochrome P450 [5,12,16]. ...
Hereditary coproporphyria (HCP) and variegate porphyria (VP) are referred to as neurocutaneous porphyrias (NCP). Data concerning their systemic presentation are limited and no direct attempt of comparison of the two has ever been made. Our aim was to describe the type and frequency of systemic manifestations of NCPs in Israeli patients. A cross-sectional survey was conducted. The study population included all patients with NCP diagnosed at the Israeli National Service for Biochemical Diagnoses of Porphyrias (INSP) between 1988 and 2019. Of the 83 patients with NCP who were alive in 2019, 61 (73%) completed the survey, 40 with VP and 21 with HCP. Systemic symptoms were reported by 63% of the VP group and 62% of the HCP group (p = .96); corresponding rates of cutaneous symptoms were 58% and 5% (p < .001). We found no association between the occurrence of systemic and cutaneous symptoms. Among patients with systemic involvement, abdominal pain was the predominant systemic symptom, found in 64% of the VP group and 69% of the HCP group; Analysis of symptom frequency showed that in 68% of the VP group, systemic symptoms (either abdominal, musculoskeletal or neuropsychiatric) occurred on a daily/weekly basis, whereas the HCP group experienced less than one symptom per week (p < .001). This nationwide study depicts a significantly heavier disease burden in VP patients compared to HCP owing to its more frequent neurovisceral and cutaneous manifestations.
