The question of the reasons for the extreme variation in morbidity among the gene carriers of acute porphyria and the great diversity of the precipitating factors are approached by the aid of a model of interacting genomic circuits. It is based on the current paradigm of the acute porphyric attack as a result of a toxic proximal overload of the enzyme-
deficient heme-biosynthetic patway. Porphyrogenic influx of precursors is seen as a consequence of uncontrolled induction of its gate-keeping enzyme, ubiquitous 5-aminolevulinate synthase (ALAS1), due to attenuated post-translational control of the enzyme combined with activated gene transcription. Focus is directed on the genomic
control of the master-regulator of ALAS1-transcription, the nuclear receptor pair constitutively active receptor (CAR) and pregnane xenobiotic receptor (PXR). On activation by their ligands, i.e. lipophilic drugs, solvents, alcohols, hormonal steroids and biocides, these DNA-binding proteins transform xenobiotic or steroid stimuli to coordinated
activations of gene transcription-programs for ALAS1 and apo-cytochromes P450 (apo-CYPs), thus effecting the formation of xenobiotic-metabolizing cytochrome P450 enzymes. The potency of the CAR/PXR-transduction axis is enhanced by co-activators generated in
at least four other genomic circuits, each triggered by different external and internal stimuli clinically experienced to be porphyroge
nic, and each controlled by co-activating and co-repressing modulators. The expressions of the genes for CAR and PXR are thus augmented by binding glucocorticoid receptor (GR) activated by a steroid hormone, e.g, cortisol generated in fasting, infection or different forms of stress. The promotor regions of ALAS1 and apoCYPs contain binding sites for at least three co-activating transcription factors enhancing CAR/PXR transduction: i.e. the ligand-independent growth hormone (GH)-pulse controlled hepatocyte nuclear factor 4 (HNF4), the insulin-responsive forkhead box class O-(FOXO) protein pathway activated in stress and infection, and the proliferator-activated receptor gamma co-activator 1 al
pha (PGC-1alpha) circuit responding to glucagon liberated in fasting. Many interactions and cross-talk take place within the tangle of genomic circuits that control ALAS1-transcription, which may explain the extreme inter- and intra-individual variability in morbidity in acute porphyria. Reasons for gender-differences are found in sex-dependent control of HPA- and GH-activity as well as in direct, or GR-mediated effects on CAR/PCR activation. Constitutional differences in individual porphyric morbidity may be discussed along lines of mutations or duplications of genes for co-activating or co-repressing nuclear proteins active at different levels within the circuits.
Porphyria experts concur that acute attacks of AIP, VP and HCP, are invariably associated with increases in urinary PBG. Reports differ, however, as to the amount of increase indicative of an acute attack. Some authors consider excretion of at least 25-fold the upper level of normal, as indicative, whereas others regard a 10-fold or even a 2-fold
increase, as sufficient indication. An additional diagnostic difficulty arises from the fact that in many individuals known to have inherited one of the acute porphyrias, PBG is persistently raised also during remission. It may be markedly elevated even in asymptomatic carriers. In the absence of a universally accepted standard for interpreting PBG results, attribution of neurovisceral or neuropsychiatric symptoms in porphyrics to an acute attack of porphyria rather than to other causes, depends largely on clinical
assessment. The aim of this work was to identify reliable criteria, which will
enable establishing or excluding an acute attack, on a biochemical basis. The study summarizes and interprets data obtained during classical neurovisceral acute attacks and latent phases in 20 patients (10 with AIP, 6 with VP, and 4 with HCP). Calculated increases in urinary PBG, with the upper limit of normal excretion, (8.8 μmol/24 h), defined as
100 %, revealed an overlap between values in the acute and latent phases, (1 to 18.5-fold and 2.3 to 51-fold, respectively). This overlap indicates that the workup in each case needs to be individualized. We achieved this goal, by using another method of calculation, in which the PBG value measured during an acute attack in a particular patient was divided by the PBG value measured in that patient’s latent phase. Increases of 2.3 to 50.5-fold were obtained, leading to the conclusion that any increase, calculated as above, of 2.3-fold and higher, may be taken as indicative of an acute attack. An additional finding, demonstrated in the study, which might be useful for supporting the diagnosis of an acute attack, is the distinct emission peak observed at 404/621 nm, in the plasma fluorometric scan of AIP and HCP patients, during an acute attack. We conclude that comparison of the urinary PBG level and plasma fluorometric scan in the acute phase to those of the latent phase in the individual patient is the key to correct, accurate and reliable biochemical diagnosis of an acute attack in a patient previously diagnosed as a porphyric. The additional tests required for confirming a patient’s first acute attack, having no data to compare with, are discussed.