The 2021 study by Karl Anderson et al (15) discussed the current testing recommendations for AHP, preferring urinary PBG over ALA as the gold standard in significance, however it was suggested to review these recommendations every 2–3 years. In our patient cohort, the most common first line of testing was also urinary ALA and/or PBG, while Whole Blood (WB) Porphyrin testing is second in frequency, without showing any actual diagnostic ability to distinguish between AHP + and AHP− patients per our data from our patient cohort. Across both genders, if we only consider ALA and/or PBG then only 56% of patients would have tested positive for AHP; overlooking the 17% of AHP + patients who tested negative for ALA/PBG but were positive for genetic testing. Furthermore, using only one value (ALA or PBG) would have only identified 17% of positive patients. Adding Total Urinary Porphyrins, Coproporphyrins and Uroporphyrins to the biochemistry testing increased our positive patient cohort from 56–74%, increasing the chance of diagnosis. The likelihood of an AHP patient testing positive based on urinary metabolites alone seems to be 50% regardless of whether they are tested during an acute attack; In our study half of all AHP + patients who were tested during an attack tested negative for urinary metabolites while half of patients tested outside of an attack also tested positive for urinary metabolites.

If we had only determined AHP status by available genetic testing, we would have captured 74% of all AHP + patients, higher than standard biochemistry (urinary ALA/PBG, 56%) alone. However, genetic testing still carries a stigma with many populations (6) and due to the relatively low clinical penetrance of around 10% (01, Bissel et al), expanding genetic tests to wider screens would potentially yield plenty of false positives.

Variants of Unknown Significance (VUS) may result in a patient not receiving the correct diagnosis (20), which plagues the diagnosis of many rare diseases, including AHP, and with the increasing ease and access that patients have to ‘at home’ genetic tests, we are likely to see more and more self-referred patients, many of may not actually have a Porphyria, or alternatively, may have subtypes or similar diseases we have not yet discovered. One of the most challenging things in clinical practice is working a patient who presents with a genetic test result in hand but who does not have a typical clinical or biochemical metabolite trail to cement the diagnosis. Even among patients who have a known pathogenic mutation in HMBS, the gene associated with AIP, not all of them experience an acute pain attack, these are known as latent porphyrics and their natural history remains poorly studied. One potential advantage of adding a targeted genetic screen for patients who present for a Porphyria evaluation may be to identify such latent porphyrics and could add substantially to our understanding of the natural history of Porphyrias. However, it is advisable to undertake this only in the setting of an academic research protocol. Clinicians who work with Porphyria know that when discussing a lower potential of having a diagnosis of AHP (e.g. when there is either just a VUS in an AHP gene or when there are no typical symptoms or elevated urinary metabolites) is more of an art than a science. There are clearly environmental and physiologic factors–dehydration, starvation, anemia, certain medications—that impact whether a patient with a bona de mutation in an AHP gene will develop an acute attack (1). Given that clinical penetrance of individual genetic mutations can be quite variable (1), it is highly likely that there are other, unidentified modifier genes and pathways. In our experience at UCLA, only about 1 in 30 patients who come for a Porphyria evaluation actually end up getting a Porphyria diagnosis. This is quite often disappointing, frustrating, and confusing for them as many patients have already been to other doctors, as well as the internet, and are pre-convinced that they have a Porphyria. They may have been told by other practitioners that they ‘most likely’ or ‘definitely’ have a Porphyria, yet the only evidence is that they have mild, non-specific elevations in the urinary metabolites or a VUS in an AHP related gene.

Focusing on both provider and patient education about AHP should help sharpen diagnostic accuracy, improve clinical care and alleviate patient anxieties. Medical providers simply need to be aware of AHP as part of the differential diagnosis of recurrent acute pain attacks (especially in women of childbearing age) and know how to screen for AHP in the appropriate clinical context. Our cohort suggests that outreach to practitioners in the fields of mental health and obstetrics/gynecology may bear the most fruit and give them a resource of where to turn if they think about AHP but do not know what to do next. Providers also need to have a basic understanding of how to interpret ‘positive’ urine metabolite results. AHP is ruled in when urine metabolites that are elevated 10–100 times during a time of acute symptoms, whereas non-specific elevations of only two to three-fold are likely the result of dietary, processing, or other environmental factors. Normal or trivially elevated urine metabolites during an acute pain attack rules out AHP and alternative diagnoses for the acute pain should be sought. On the other hand, if urine metabolites are normal or trivially elevated during an asymptomatic period this does not rule out AHP. So, it is very important that we ‘leave the door’ open for this last subset of patients and avoid dismissing or minimizing patients’ concerns and knowing that there are some patients out there who are latent porphyrics. We typically give these patients a prescription for appropriate urine tests to keep in their purse or wallet so that, in the future, if they present to a healthcare facility with symptoms suggestive of AHP, they can give the provider the correct tests to order. We also encourage the patients to invite their acute care provider to contact us to discuss the case, further testing, and supportive care.