Porphyrins and the porphyrias

Abstract

This special issue of Liver International is focussed on the porphyrias, a fascinating group of mainly inherited metabolic disorders of haem metabolism. They can present to multiple medical specialties from emergency medicine to dermatology to paediatrics and because they are rare, diagnosis is frequently delayed. Although clinical trainees are often told ‘When you hear hoofbeats think horses, not zebras’ rare diseases are relatively common, affecting approximately 1 in 17 of the population at some time in their lives.¹ This means that there are a lot of ‘zebras’ presenting clinically, amongst them patients with porphyria.

The porphyrias result from overproduction of pathway intermediates, which are either predominantly from the liver, the hepatic porphyrias or from the bone marrow, the erythropoietic porphyrias. The increased metabolites have their main effects on the skin (cutaneous porphyrias) or the neurological system (the acute porphyrias). The hepatologist may be involved in investigating and managing not only the hepatic porphyrias, but also in treating complications caused by some of the erythropoietic porphyrias.

These conditions have long fascinated clinicians and scientists because of the distinct observable features, particularly the excretion of vividly coloured urine, but also the striking cutaneous manifestations. It is now 150 years since the first case of congenital porphyria was reported in the literature and the first article in this issue,² written by a group of authors with a long history of working in the field, charts developments from these early years of chemistry and clinical descriptions through the unravelling of the biochemical pathway and its regulation, to the current genomic era. The review finishes around the early 2000's, allowing the authors of the individual articles in this issue to cover more recent developments in their papers. We hope that this historical review serves as a reminder to those currently active in the field of the challenges faced by past colleagues who did not have access to current diagnostic technology and the certainty provided by recent genomic developments.

In keeping with this historical review, it also seems fitting in this editorial to remember two clinician scientists who passed away recently having made a substantial contribution to the porphyria field. Professor Joseph Bloomer (1940–2021) was a distinguished American physician-scientist and leader in the study of liver disease, particularly in relation to erythropoietic protoporphyria (EPP). His collaborative research included developing diagnostics and spearheading research that identified the enzyme abnormalities in EPP and variegate porphyria (VP). Professor Manfred Doss (1935–2022) an eminent German clinician–scientist worked on porphyria for over five decades and made significant contributions to clinical practice and diagnostics. His most widely recognized contribution being the discovery in 1979 of the autosomal recessive acute porphyria, ALA dehydratase deficiency porphyria, previously known as Doss porphyria.

The second article in this series deals with heme biosynthesis and its regulation. Belot and colleagues provide a comprehensive and updated overview of this process, pinpointing the genetic defects that define the different types of porphyrias.³ Recent evidence demonstrating the presence of heme transporters in organelle and cellular membranes suggest that cells and organs might share heme to maintain cellular heme levels. These findings could open future therapeutic alternatives not only for the porphyrias, but also for cancer, obesity, diabetes and neurodegenerative or muscular disorders.

The following article by Balwani and colleagues introduces us into the art of telling zebras from horses, particularly for the acute hepatic porphyrias (AHPs).⁴ Using a case-based format, the authors illustrate how clinical and biochemical evidence is leveraged to deliver an accurate diagnosis. The latest recommendations on the therapeutic management and monitoring of patients with sporadic and recurrent acute attacks are also discussed. The final sections deal with surveillance for the common complications associated with AHPs and the importance of cascade genetic testing to identify other affected family members and allow counselling about the condition.

The next two articles delve into the long-term complications of AHPs, as well as the role of liver transplantation (LT) in patients with EPP who suffer liver failure as a complication and for AHP patients with recurrent attacks that are refractory to the available therapy.^{5, 6} The role of haematopoietic stem cell transplantation as curative option after LT in EPP patients is highlighted by Lissing and colleagues. These authors also emphasize the high risk of primary liver cancer development in patients with a history of active acute intermittent porphyria and strongly recommend their inclusion in bi-annual surveillance programs after the age of 50.⁶ Besides this, lifestyle management and regular monitoring of blood pressure, kidney function and cardiovascular risk factors to allow early preventative interventions is proposed by Pischik and coauthors, who advocate for personalized monitoring tailored to patients age, their comorbidities and disease activity.⁵

Minder and her coauthors review the increasingly complex subgroup of protoporphyrias. They provide a commendable overview of the genetic defects leading to EPP1, X-linked EPP and CLPX-protoporphyria (designated EPP-2 in OMIM), along with their diagnostic workup and management of skin and hepatic manifestations. The latest strategies in disease monitoring and therapeutic approaches for these patients are thoroughly discussed.⁷

Next, To-Figueras and colleagues move from zebras to almost unicorns in their article on the ultra-rare congenital erythropoietic porphyria. The authors revisit the history of the disease, comprehensively reviewing its genetic and biochemical characteristics, clinical manifestations and diagnosis, including the rarest forms. A critical appraisal of current and emerging therapeutic strategies is also provided.⁸ Leaving the realm of unicorns, Sarkany and Philips provide an excellent update on the diagnosis and clinical management of another hepatic porphyria, porphyria cutanea tarda (PCT). Although PCT is the commonest of the porphyrias, it is still not a horse, and early diagnosis is critical to early intervention with specific treatment in order to normalize circulating porphyrins and allow the skin to recover. It also allows identification and treatment of the hepatic disorder damaging the liver reducing the risk of liver or biliary tract cancer and improving life expectancy.⁹

The article of Jericó and colleagues provides a detailed overview of current and emerging therapies for hepatic and erythropoietic porphyrias. Strategies ranging from the use of small molecules, gene therapy and mRNA-based therapies are cogently summarized. The advantages of emerging approaches in delivering personalized treatments for porphyria patients, and their inherent potential risks are highlighted.¹⁰ This special issue concludes with the cutting-edge review by Aarsand and collaborators on the critical role played by standardized biochemical testing in the accurate diagnosis of porphyrias.¹¹ The authors highlight the strengths and weaknesses of the various analytes used and the limitations of genetic testing as the initial test.

Over the past 25 years, research on porphyrias has grown exponentially, leading to substantial advancements in their understanding and diagnosis, also paving the way for innovative therapeutic approaches for these orphan diseases. Recent advancements in these conditions will be presented at the International Congress of Porphyrins and Porphyrias (ICPP), which will take place at the University of Navarra in Pamplona, Spain, from 21 to 25 September 2024 (https://icpp2024.com/). The ICPP congress (Figure 1), held every 2 years, brings together leading experts from around the world to share progress in diagnostics, lifestyle management and improve patient care, treatments and guidelines related to porphyrias. Only through rigorous research and generous scientific collaboration will we one day fully understand these fascinating conditions and be able to reliably pick out the zebra from the horses, even in the dark.

The authors do not have any disclosures to report.