The long-term complications involve chronic kidney disease, chronic hypertension, hepatocellular carcinoma, polyneuropathy and depression and anxiety. Management involves lifestyle and nutrition modification, treatment of acute attacks with glucose or hemin (triggering negative feedback of ALAS), and treatment of symptoms with appropriate medication for pain, nausea and vomiting. Preventive medication includes gonadotropin-releasing hormone agonists, intravenous hemin, and subcutaneous givosiran, a gene-silencing small interfering RNA (siRNA) directed towards ALAS, which was approved for use by the U.S. Food & Drug Administration in 2019 and has only recently been used in Europe and the UK [2, 3].
Because AHP is rare and presentation is variable and often intermittent, diagnosis is often delayed or missed. This can result in mismanagement, including the prescription of medications that exacerbate the condition. Laboratory diagnostic testing provides definitive results but only when the correct tests are ordered. Testing standards and guidelines have been developed in recent years in the UK, Europe and Australia, and recommendations have been published in the USA [4–7].
Testing a random urine sample for PBG is sufficient to diagnose AHP. Testing for ALA concentrations is no longer needed for diagnosis of AHP, but is useful for discerning tyrosinemia or lead poisoning. In an acute attack, PBG concentrations will be grossly elevated, reaching 10 to 150 times the upper limit of the reference interval and a diagnosis of porphyria is clear [4, 8]. This first-line screening is carried out as the range of symptoms of AHP is so varied and can be caused by other conditions and is often done to rule out AHP. As acute attack of AIP can be life threatening and treatment needs to be started as soon as possible, PBG testing should be carried out on a random (non-timed) urine sample to avoid the delays in diagnosis that can occur with a 24-hour (or total) urine collection. However, if PBG is not elevated but a strong clinical suspicion of porphyria remains, then urine porphyrins should be analysed to prevent a missed diagnosis of VP or HCP, where PBG levels are less elevated and return to normal more quickly [4, 7]. Following a positive first-line test or continued strong suspicion of porphyria, second-line or confirmatory testing should be done to identify the exact type of porphyria. This requires analysis of the original urine sample, EDTA whole blood and feces at (in the UK and Europe) a specialist porphyria lab. Typical results of second-line testing are shown in Table 1. Recommended testing algorithms can be seen in Woolf et al., Anderson et al. and the ARUP Laboratories website [4, 7, 9].
Quantitative analysis of PBG frequently is performed using ion-exchange chromatography followed by reaction with Ehrlich’s reagent and spectrophotometric detection and was often done using the PBG by Column Test Porphobilinogen kit (Bio-Rad) until its withdrawal from the market. A current alternative is the ClinEasy® Complete Kit for Porphobilinogen in Urine (iris tech/ Recipe). However, rapid and cost-effective in-house tests can be developed using ion-exchange spin columns, as detailed by Roshal et al.  and Balogun et al.  who also reassessed reference intervals by the analysis of 10 years of de-identified retrospective PBG results.
It is recommended that confirmatory quantitative porphyrin analysis is done in specialist porphyria laboratories that can maintain appropriate staff training and accreditation along with participation in appropriate internal quality control and external quality assessment schemes. This analysis is accomplished using high performance liquid chromatography and fluorescence spectrometry or mass spectrometry techniques [4, 12, 13].
The analytes are light sensitive and therefore need to be protected from light, by collection in amber-coloured tubes or in tubes wrapped in tin foil or black plastic. Samples should be stored at 4°C and are stable for up to four days; feces may also be frozen if sample collection happens before a weekend or bank holiday. Repeated freezethaw cycles should be avoided. If samples need to be sent on to a specialist lab, shipping should happen within 24 hours of collection . As the main specimen type is urine, a waste product that can vary notably in concentration, all quantitative urine results should be reported as a ratio to urine creatinine concentration. Additionally, testing should be carried out on urine samples with creatinine concentrations of at least 2 mmol/L.
Until the 1980s, mortality from acute attacks of porphyria was approximately 25%; however, with early diagnosis and proper treatment, prognosis has much improved. However, a burden of chronic disease in AIP patients is common – particularly chronic liver and kidney disease, and an increased risk of hepatocellular carcinoma in older patients. Now, however, once the porphyria subtype has been identified by biochemical confirmatory testing, the advent of improved gene sequencing technologies allows the identification of the genetic mutation responsible. This can be followed by genetic counselling and mutational analysis of family members, which can identify low levels of disease that might have otherwise been missed or misdiagnosed, and appropriate lifestyle changes/treatment will prevent the accumulation of low levels of chronic disease. Additionally, there is the exciting new development of siRNA therapy givosiran (Alnylam) directed against ALAS, which is now being funded by the NHS in the UK and has revolutionary consequences for the recipients .