Variations in Porphobilinogen and 5-Aminolevulinic Acid Concentrations in Plasma and Urine from Asymptomatic Carriers of the Acute Intermittent Porphyria Gene with Increased Porphyrin Precursor Excretion

Flodérus, Ylva; Sardh, Eliane; Möller, Christer; Andersson, Claes; Rejkjær, Lillan; Andersson, D. E. H.; Harper, Pauline

doi:10.1373/clinchem.2005.058198

Cited by 54 publications

(65 citation statements)

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“…In AIP, which accounts for most attacks of acute porphyria (1,11 ), heme precursor excretion may become typical during clinical remission, and the PBGD assay in such cases does not adequately discriminate between affected and nonaffected individuals (12 ). The different investigative strategies that are available use various combinations of metabolite-, enzyme-, and DNA-based methods (1,(13)(14)(15)(16), but there is only limited information about diagnostic accuracy to support the selection of particular strategies (12,(17)(18)(19).…”

mentioning

confidence: 99%

Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene

et al. 2009

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Background: Clinically indistinguishable attacks of acute porphyria occur in acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). There are few evidence-based diagnostic strategies for these disorders. Methods: The diagnostic sensitivity of mutation detection was determined by sequencing and gene-dosage analysis to search for mutations in 467 sequentially referred, unrelated patients. The diagnostic accuracy of plasma fluorescence scanning, fecal porphyrin analysis, and porphobilinogen deaminase (PBGD) assay was assessed in mutation-positive patients (AIP, 260 patients; VP, 152 patients; HCP, 31 patients). Results: Sensitivities (95% CI) for mutation detection were as follows: AIP, 98.1% (95.6%–99.2%); HCP, 96.9% (84.3%–99.5%); VP, 100% (95.7%–100%). We identified 5 large deletions in the HMBS gene (hydroxymethylbilane synthase) and one in the CPOX gene (coproporphyrinogen oxidase). The plasma fluorescence scan was positive more often in VP (99% of patients) than in AIP (68%) or HCP (29%). The wavelength of the fluorescence emission peak and the fecal coproporphyrin isomer ratio had high diagnostic specificity and sensitivity for differentiating between AIP, HCP, and VP. DNA analysis followed by PBGD assay in mutation-negative patients had greater diagnostic accuracy for AIP than either test alone. Conclusions: When PBG excretion is increased, 2 investigations (plasma fluorescence scanning, the coproporphyrin isomer ratio) are sufficient, with rare exceptions, to identify the type of acute porphyria. When the results of PBG, 5-aminolevulinate, and porphyrin analyses are within reference intervals and clinical suspicion that a past illness was caused by an acute porphyria remains high, mutation analysis of the HMBS gene followed by PBGD assay is an effective strategy for diagnosis or exclusion of AIP. .

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confidence: 99%

Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene

et al. 2009

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“…For example, serum ALA levels are elevated in lead poisoning, hereditary tyrosinema and the acute porphyrias. Consequently, a number of groups have reported methods for ALA determination in biological samples [32,33]. More recently, ALA has been applied topically for the diagnosis and treatment of premalignant and malignant skin lesions.…”

Section: Discussionmentioning

confidence: 99%

Practical Considerations in the Pharmaceutical Analysis of Methyl and Hexyl Ester Derivatives of 5-Aminolevulinic Acid

Morrow¹,

McCarron²,

Woolfson³

et al. 2009

TOACJ

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Photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA), a water-soluble precursor of the potent endogenous photosensitiser, protoporphyrin IX (PpIX), is a treatment and diagnostic tool for premalignant and malignant skin cancers. However, to improve drug delivery to deeper skin lesions, more lipophilic ALA esters have been investigated. Owing to the necessity in drug delivery research for efficient and validated assays for ALA esters in solution, this paper aims to describe optimised protocols to quantify the methyl and hexyl esters of ALA.ALA esters were derivatised using acetyl acetone and formaldehyde reagents and analysed using reversed phase HPLC. For the first time, the significance of ALA-impurities in ester samples has been highlighted. Furthermore, it was shown that for a given concentration, peak areas obtained for ALA-esters were significantly smaller than those obtained for ALA (p < 0.05). This may be due to parent drug undergoing the derivatisation reaction more efficiently or because the ALAderivate is inherently more fluorescent than the ester derivatives. The method was optimised to give acceptable intra-and inter-day variability (CV values < 5%) and the limits of detection and quantification were determined for both drugs.The validated methods were used to determine the release profiles of ALA, m-ALA and h-ALA from an o/w cream formulation. The percentage of drug loading released after five hours across a model membrane was in the order of ALA (45.2%) > m-ALA (38.3%) > h-ALA (33.9%). These findings may explain why, historically, some of the benefits seen with ALA-esters using cell culture models have not been demonstrated in vivo.

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“…The diagnostic interpretation of these tests is easier during the symptomatic phase (acute crisis) of the disease; in contrast, during remission the tests may partially lose their diagnostic specificity and sensitivity, making more difficult the diagnosis in absence of a specialist's evaluation and specific genetic tests [38]. Nevertheless, biochemical methods still remain indispensable to monitor the level of activity of the disorder, and to evaluate the risk of development of the organ diseases (liver and kidney), associated with porphyria [11].…”

Section: Diagnosismentioning

confidence: 99%

“…Besides the diagnostic confirmation for symptomatic patients and the evaluation of the association between genotype and phenotype (i.e. the clinical significance of each single gene mutation), genetic assessment has a key role in family studies (identification of asymptomatic carriers in kindred): asymptomatic carriers may remain completely undiagnosed in absence of genetic screening, due to the low clinical penetrance of the genetic defect (even \25% for AIP), as mentioned above [9,38,39]. The risk of developing potentially acute and life-threatening fatal attacks even in these asymptomatic carriers if exposed to possible precipitating factors (including certain medical treatments or causing unnecessary surgical procedures) makes it essential to exclude or confirm the diagnosis of porphyria in all relatives, whenever it has been diagnosed in any family member.…”

Section: Diagnosismentioning

confidence: 99%

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

2009

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The porphyrias are a heterogeneous group of metabolic diseases resulting from a variable catalytic defect of one of the eight enzymes involved in the heme biosynthesis pathway; they are mostly inherited diseases, but in some circumstances the metabolic disturbance may be acquired. The specific patterns of tissue overproduction (and hence accumulation and excretion) of toxic heme precursors, associated with each enzymatic deficiency, are responsible for the characteristic biochemical and clinical features of each of these diseases. Moreover, even in the presence of a specific inherited enzymatic defect, many different environmental factors (such as drugs, calorie restriction, hormones, sunlight exposition, infections, etc.) often play a key role in triggering the clinical expression of the various forms of porphyrias. The porphyrias are often misdiagnosed diseases, due their multiform clinical manifestations, able to mimic many other more common diseases. For this reason, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially for the forms presenting with acute and life-threatening clinical features. According to the clinical features, the porphyrias can be classified into neuropsychiatric (characterized by neurovisceral crises involving autonomic and central nervous system but also the liver and the kidney with possible consequences in terms of neurological, psychic, cardiac, respiratory, liver and kidney functions), dermatological (mostly presenting with cutaneous lesions due to photosensitivity), and mixed forms. From a strictly clinical point of view, porphyrias presenting with neurovisceral attacks are also referred as acute porphyrias: they are the object of the present review. An accurate diagnosis of acute porphyria requires knowledge and the use of correct diagnostic tools, and it is mandatory to provide a more appropriate therapeutic approach and prevent the use of potentially unsafe drugs, able to severely precipitate these diseases, especially in the presence of life-threatening symptoms. To date, availability of a relatively stable haem preparation (haem arginate) has significantly improved the treatment outcome of acute porphyric attacks, so the knowledge about the diagnosis and the management of these diseases may be relevant for physicians working in internal medicine, neurology and emergency units.

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Variations in Porphobilinogen and 5-Aminolevulinic Acid Concentrations in Plasma and Urine from Asymptomatic Carriers of the Acute Intermittent Porphyria Gene with Increased Porphyrin Precursor Excretion

Cited by 54 publications

References 15 publications

Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene

Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene

Practical Considerations in the Pharmaceutical Analysis of Methyl and Hexyl Ester Derivatives of 5-Aminolevulinic Acid

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

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