Understanding the Clinical Spectrum of the Cutaneous and Acute Hepatic Porphyrias

Abstract

Porphyrias are rare metabolic disorders caused by inherited or acquired enzymatic defects in the heme biosynthesis pathway, resulting in the accumulation of heme precursors or toxic porphyrin intermediates. The cutaneous porphyrias arise from enzymatic defects in later steps of the heme biosynthesis pathway, which lead to the build-up of photoactive porphyrins in the skin and liver, such as coproporphyrins, protoporphyrins, and uroporphyrins. These photoactive porphyrins generate reactive oxygen species that drive the characteristic cutaneous manifestations, including painful photosensitivity, skin fragility, and blistering. The cutaneous porphyrias encompass both blistering and non-blistering subtypes, which include erythropoietic protoporphyria, X-linked protoporphyria, congenital erythropoietic porphyria, porphyria cutanea tarda, and hepatoerythropoietic porphyria, each distinguished by specific biochemical patterns and clinical features. Acute hepatic porphyrias, which include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficiency porphyria, result in the accumulation of neurotoxic precursors, such as δ-aminolevulinic acid and porphobilinogen. While acute neurovisceral attacks predominate in acute hepatic porphyrias, certain subtypes, such as variegate porphyria and hereditary coproporphyria, may present with blistering photosensitivity, creating a significant diagnostic overlap between cutaneous porphyrias and other photodermatoses. This overlap underscores the importance of awareness of acute hepatic porphyrias among dermatologists, who may be the first clinicians to encounter patients with these disorders. In addition, recent treatment breakthroughs will likely bring patients with porphyrias to pursue care, changing the likely underestimated disease prevalence rates. This narrative review provides a comprehensive overview of the pathobiology, clinical features, diagnostic strategies, and management approaches for the cutaneous and acute hepatic porphyrias.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40257-026-01046-x.

Introduction

Porphyrias comprise a group of rare, inherited, or acquired disorders resulting from different enzymatic defects in heme biosynthesis [1, 2]. The synthesis of heme requires a regulated eight-step enzymatic pathway [1]. Disruption of any enzyme within this pathway, whether through genetic mutation or acquired inhibition, leads to an accumulation of upstream heme precursors or porphyrins [1]. The specific intermediates that accumulate, and the cellular compartment in which they do so, determine the clinical manifestations of each porphyria subtype [1]. Accordingly, porphyrias are broadly categorized as hepatic or erythropoietic based on the primary site of precursor accumulation [2]. They may also be categorized into acute hepatic porphyrias (AHPs) and cutaneous forms, with the cutaneous porphyrias further classified into blistering and non-blistering subtypes [3]. Acute hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP) (Fig. 1). The cutaneous porphyrias are erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and hepatoerythropoietic porphyria (HEP) [Fig. 1].

Fig. 1.

Heme biosynthesis pathway and associated cutaneous and acute hepatic porphyrias

Deficiencies in enzymes involved in the early steps of the heme biosynthesis pathway, including ALAD and porphobilinogen deaminase, lead to the accumulation of neurotoxic precursors such as δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) [2, 4]. While each AHP is genetically distinct and deficient in key enzymes, they all share the characteristic clinical feature of acute neurovisceral attacks from the accumulation of porphyrin precursors, particularly ALA and PBG [4]. These attacks typically present with severe abdominal pain, nausea, vomiting, and constipation, as well as peripheral neuropathy [4]. Along with these neurovisceral symptoms, certain subtypes manifest with cutaneous findings that may prompt dermatologic evaluation, making the AHPs relevant to the practicing dermatologist. For instance, patients with both VP or HCP may present with blistering photosensitivity [5, 6]. Increased awareness of the AHPs among dermatologists is critical for differentiating these disorders from cutaneous porphyrias and other photodermatoses, as this distinction informs triage, appropriate specialty care, and timely management. According to the American Gastroenterological Association, diagnostic delays in AHPs frequently exceed 15 years, underscoring the importance of early recognition and evidence-based management to prevent long-term morbidity associated with AHPs [4].

Defects of enzymes involved in later steps of the heme biosynthesis pathway, including ferrochelatase (FECH), uroporphyrinogen III synthase (UROS), uroporphyrinogen III decarboxylase (UROD), protoporphyrinogen oxidase (PPOX), and coproporphyrinogen oxidase (CPOX), cause the build-up of photoactive porphyrins, such as coproporphyrins, protoporphyrins, and uroporphyrins [2, 4]. Following exposure to visible light, these photoactive intermediates absorb visible light energy, creating reactive oxygen species, resulting in the acute painful phototoxic reactions, skin fragility, and subepidermal blistering seen in cutaneous porphyrias [7]. The clinical course may be further complicated by hepatic dysregulation and iron dysfunction through the complex interplay between impaired heme biosynthesis, reduced iron absorption and supply, and accumulation of porphyrins in the liver [7, 8]. Erythropoietic protoporphyria and XLP are characterized by non-blistering photosensitivity, while CEP, PCT, and HEP are characterized by blistering photosensitivity [7]. Because of the accumulation of photoactive porphyrins in the skin, the cutaneous porphyrias are characterized by chronic cutaneous photosensitivity rather than acute neurovisceral attacks, which are characteristic of AHPs [7]. Persistent photosensitivity can lead to chronic skin damage and impair quality of life, underscoring the need for timely diagnosis and management [9].

Given the heterogeneity in biochemical patterns and nonspecific clinical presentations of porphyrias, patients with these disorders often face diagnostic delays [10]. Though rare, porphyrias remain clinically important as the variation in disease presentation is poorly understood, leading to frequent diagnostic delays and inconsistent management across subtypes. A clearer understanding of the biochemical and clinical diversity among porphyrias is essential to improve recognition, guide precise diagnosis, and inform targeted therapeutic approaches. We conducted a narrative review to synthesize current knowledge of porphyria pathobiology, clinical features, and strategies for diagnosis and management.

Methods

A structured literature search was conducted across PubMed, Google Scholar, Scopus, and ScienceDirect, and the Wiley Online Library to identify studies relevant to the biochemical mechanisms, clinical manifestations, diagnosis, and management of the porphyrias. The search strategy employed a combination of keywords, including “porphyria,” “heme biosynthesis,” “acute hepatic porphyria,” “cutaneous porphyria,” “porphyrin metabolism,” “phototoxicity,” “ALA,” “PBG,” and “heme synthesis disorders.” Studies were included if they were published in English in peer-reviewed journals and were available from January 1980 through December 2025.

The initial search yielded 1212 unique records. Two independent reviewers assessed the titles and abstracts of these citations for relevance. After removal of 102 duplicate entries and exclusion of 247 records using automated filters for non-peer-reviewed content, conference abstracts, and non-English publications, 863 records proceeded to title and abstract screening. 768 records were excluded for reasons including non-porphyria disease focus (n = 195), lack of relevance to porphyria pathophysiology (n = 171), insufficient mechanistic detail (n = 137), nonspecific discussion of photosensitivity or hepatic dysfunction (n = 89), lack of a clinical correlation (n = 75), absence of diagnostic or management relevance (n = 64), and incomplete full-text availability (n = 37). Ultimately, 95 studies met inclusion criteria and were incorporated into the final synthesis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adapted to ensure a transparent structured literature search, and findings were synthesized thematically (Fig. 1 of the Electronic Supplementary Material).

Cutaneous Porphyrias

Erythropoietic Protoporphyria (EPP)

Pathobiology

Erythropoietic protoporphyria is a non-blistering cutaneous porphyria caused by a deficiency of FECH, the final enzyme in the heme biosynthesis pathway that inserts ferrous iron into protoporphyrin IX (PPIX) to make heme [7, 11]. Erythropoietic protoporphyria is characterized by the accumulation of metal-free PPIX in erythrocytes, plasma, and the skin due to erythroid production of PPIX exceeding FECH capacity for conversion [11, 12]. The highly photosensitizing PPIX is lipophilic and readily moves from red blood cells into subcutaneous tissue [1]. Following sunlight exposure, PPIX absorbs visible light and ultraviolet A radiation to form reactive oxygen species, damaging endothelial and subcutaneous tissues and triggering inflammatory responses [7, 13, 14]. This phototoxic mechanism is the basis of the acute painful non-blistering photosensitivity that defines EPP. Although most reactions are precipitated by natural sunlight, these phototoxic episodes may also occur with artificial light sources that emit wavelengths capable of activating PPIX, such as those used in surgical or dental procedures [1].

Inheritance and Epidemiology

Erythropoietic protoporphyria most commonly results from a pathogenic FECH variant on one allele and is typically inherited in an autosomal dominant pattern with incomplete penetrance [15]. Less commonly, EPP may also be inherited in an autosomal recessive pattern when biallelic pathogenic FECH variants are present [15]. A French cohort study found the prevalence of autosomal dominant EPP as 95% (95% confidence interval 91–99), whereas the prevalence of autosomal recessive EPP was 4% (95% confidence interval 1–8). In 97.9% of patients with EPP with autosomal dominant inheritance, a pathogenic FECH variant on one allele was inherited in trans with a common hypomorphic IVS3-48C allele that affects aberrant splicing and reduces FECH activity [15]. Another cohort study found that the IVS3-48C allele modulated the phenotypic expression of EPP in South African patients with EPP when compared with matched controls [16]. Clinical manifestations of dominant EPP occur when FECH activity falls below the expected 50%, underscoring the role of gene polymorphisms, such as IVS3-48C, in the clinical expression of EPP [17]. Accordingly, the clinical prevalence of EPP reflects the geographic distribution of the hypomorphic IVS3-48C allele, with a higher prevalence reported in Europe, North America, Japan, and southeast Asia, and a lower prevalence reported in West Africa [15]. As such, differences in the frequency of gene polymorphisms, along with potential protective effects of increased eumelanin levels, may contribute to these observed epidemiologic patterns [1, 15].

Clinical Features

Clinically, EPP presents in early childhood, with prodromal symptoms including tingling, burning, and itch of sun-exposed skin following minutes of sun exposure [1] (Table 1). With continued sun exposure, these symptoms can progress to severe phototoxic reactions characterized by erythema, purpura, and edema, and severe recalcitrant pain often affecting the hands, face, and feet [7] (Fig. 2). Unlike the blistering seen in VP, HCP, CEP, PCT, or HEP, EPP is characterized as non-blistering, although blistering may occur in severe reactions and is less common [1]. This photosensitivity may lead to hyperkeratosis, lichenification, and scarring of sun-exposed skin over time [1]. With repeated phototoxic reactions, patients may develop characteristic cobblestone-like changes of the nasal bridge and knuckles, reflecting chronic cutaneous injury [1]. Erythropoietic protoporphyria carries significant risks for anemia and iron deficiency, likely due to the complex interplay between impaired heme biosynthesis from FECH deficiency and reduced iron absorption and supply [8]. The risk of protoporphyric liver damage is also increased, as the hydrophobic nature of protoporphyrins causes excretion through bile and subsequent accumulation of protoporphyrin in the liver rather than urine, leading to hepatic dysfunction [11]. The accumulation of protoporphyrins in the liver results in liver failure in 2–5% of cases [18]. In addition, increased biliary excretion of protoporphyrin predisposes patients to cholelithiasis, which may necessitate a cholecystectomy. A prospective cohort study found that 22.1% of patients with EPP had gallstones, and 86.7% of those patients had undergone a cholecystectomy [18].

Table 1.

Summary of key characteristics, diagnosis, and management of cutaneous porphyrias

Porphyria	Inheritance	Gene (defected enzyme)	Key accumulated porphyrins	Key clinical symptoms and features	Diagnosis	Treatment and management	Long-term monitoring
Non-blistering cutaneous porphyrias
Erythropoietic protoporphyria	Autosomal dominant [15]	FECH (ferrochelatase) [11]	Metal-free protoporphyrin IX [12]	Immediate non-blistering photosensitivity within minutes of sun exposure (often involving hands, face, and feet) [1, 7]; early childhood onset [1]	Elevated total erythrocyte protoporphyrins (85–100% present as metal free) [12]; confirmation with genetic testing of FECH [11]	Photoprotection and sun avoidance [7]; vitamin D and iron supplementation [19]; afamelanotide [23]; liver and bone marrow transplantation in severe hepatic disease [7, 26]	Hemoglobin, iron, erythrocyte protoporphyrin levels, liver function [8, 18]; vitamin D levels [19]
X-linked protoporphyria	X-linked dominant [31, 32]	ALAS2 (5-aminolevulinate synthase 2) [28, 29]	Protoporphyrin IX (proportion of metal-free protoporphyrin IX is lower compared with EPP) [12, 19]	Immediate non-blistering photosensitivity within minutes of sun exposure (often involving hands, face, and feet) [5]; early childhood onset [5]	Elevated total erythrocyte protoporphyrins (50–85% present as metal free) [12, 19]; confirmation with genetic testing of ALAS2 [19, 28]	Photoprotection and sun avoidance [7]; vitamin D and iron supplementation [19]; afamelanotide [23]; liver and bone marrow transplantation in severe hepatic disease [7]	Hemoglobin, iron, erythrocyte protoporphyrin levels, liver function [32]; vitamin D levels [19]
Blistering cutaneous porphyrias
Congenital erythropoietic porphyria	Autosomal recessive [37]	UROS (uroporphyrinogen III synthase) [11]; rarely GATA1 (GATA1) [38]	Coproporphyrin I, uroporphyrin I [35, 36]	Blistering photosensitivity and skin fragility beginning at birth or in infancy [7, 35]; red urine erythrodontia, corneal ulcers, hemolytic anemia [7, 38]	Elevated uroporphyrins and coproporphyrins in urine, plasma, and erythrocytes, coproporphyrins elevated in stool [7, 35]; confirmation with genetic testing of UROS [37]	Photoprotection and sun avoidance [11]; blood transfusion [34]; phlebotomy therapy, iron chelation [40, 41]; bone marrow transplantation in severe disease [37, 42]	Hemoglobin, reticulocytes, iron, bilirubin, liver function [35]; iron profiles in transfusion dependence to evaluate for iron overload [34, 35]
Porphyria cutanea tarda	Type I is sporadic [47]; type II is autosomal dominant [50]	Type I involves the acquired hepatic inhibition of uroporphyrinogen III decarboxylase [48]; type II affects UROD (uroporphyrinogen III decarboxylase) [50]	Uroporphyrins, heptacarboxyl porphyrins [53]	Blistering photosensitivity and skin fragility (often involving dorsal hands, forearms, and face) [7]; adult onset [7]	Elevated plasma and urine porphyrins (predominance of uroporphyrin and heptacarboxyl porphyrins) [53]; confirmation of familial disease with UROD genetic testing [11, 53]	Phlebotomy therapy [46, 55]; low-dose hydroxychloroquine [46, 57]; avoidance of susceptibility factors such as smoking, alcohol use, estrogen use, HIV, hepatitis C, hemochromatosis, and iron overload [48, 49]; hepatitis C antiviral therapy [58]	Serum ferritin levels to evaluate for relapse following phlebotomy therapy [56]; urine and plasma porphyrins to evaluate for recurrence [46]
Hepatoerythropoietic porphyria	Autosomal recessive [59]	UROD (uroporphyrinogen III decarboxylase) [7]	Uroporphyrins, heptacarboxyl porphyrins [62, 66]	Blistering photosensitivity and skin fragility (often involving dorsal hands, forearms, and face) [7, 65]; red urine, erythrodontia, ocular damage [5, 62]; childhood onset (often before 2 years of age) [7]	Elevated total porphyrins in urine or plasma (increased uroporphyrins and heptacarboxyl porphyrins) [62, 66]; elevated erythrocyte zinc protoporphyrin levels [48, 62]; confirmation with genetic testing for biallelic pathogenic variants in UROD [67]	Photoprotection and sun avoidance, avoidance of susceptibility factors such as smoking, alcohol use, estrogen use, HIV, hepatitis C, hemochromatosis, and iron overload [5, 62]	Urine and plasma porphyrins [62]

EPP erythropoietic protoporphyria

Fig. 2.

Linear erosions affecting the lateral nasal bridge and lower lip in a patient with erythropoietic protoporphyria. Clinical photograph courtesy of Horner et al. [53]

Diagnosis

Diagnosis of EPP relies on biochemical confirmation of markedly elevated total erythrocyte protoporphyrins approximately three to four times the upper limit of normal, with 85–100% present as metal-free protoporphyrin [12]. The remaining fraction is metal chelated, whereas XLP is distinguished by a lower metal-free proportion, typically 50–85% [19]. Given that protoporphyrin is not water soluble, excess protoporphyrin is excreted into bile and feces rather than urine; therefore, urinary protoporphyrin levels remain normal, whereas stool protoporphyrin levels may be increased but should not be used as a diagnostic criterion [11]. Direct measurement of whole-blood metal-free PPIX has been used in clinical trial settings but its utility in routine clinical diagnosis remains limited [20]. Genetic testing of FECH helps confirm the diagnosis and distinguish EPP from XLP, though the presence of unknown variants means that a negative genetic result cannot completely exclude EPP [11, 19].

Treatment and Management

Treatment and management of EPP focus on photoprotection and sun avoidance, prevention of hepatic complications, and improvement of functional quality of life. Broad-spectrum or tinted sunscreens with visible light blockers can help minimize phototoxic injury, but sun avoidance and photoprotective clothing are historically the most effective options [7]. Smaller studies, case series, and uncontrolled trials have evaluated additional therapeutic approaches, including ultraviolet phototherapy and beta carotene supplementation [21]. These interventions have not been studied in large randomized clinical trials, and reported outcomes have been variable [21]. In addition, cimetidine for protoporphyria has been evaluated in a phase II clinical trial; however, evidence supporting its clinical use remains limited, as prior reports are primarily case series suggesting potential improvements in PPIX levels and phototolerance, with no comparative studies demonstrating efficacy [11, 22]. Afamelanotide, a synthetic α-melanocyte stimulating hormone agonist delivered via a subcutaneous implant, has emerged as a key therapy approved by the US Food and Drug Administration for EPP and XLP, upregulating eumelanin production and antioxidant activity and limiting photoactive protoporphyrin activity [1, 23]. Additionally, dersimelagon is an oral, selective, melanocortin 1 receptor agonist currently under phase III clinical development that has demonstrated significant improvements in the duration of symptom-free sun exposure in patients with EPP or XLP [11, 24]. Bitopertin, an oral erythroid glycine transporter-1 inhibitor in phase II clinical development, has also shown a marked reduction in PPIX in erythroid cells and patients with EPP [20, 25]. Liver transplantation is warranted when disease progresses to liver failure, and bone marrow transplantation is curative in EPP but is generally reserved for severe hepatic disease or following liver transplantation to prevent EPP recurrence [7, 26]. Hepatitis A and B vaccinations are also advised to avoid preventable liver damage [11]. Transient elastography, a non-invasive ultrasound-based procedure, may be considered to assess patients with EPP at risk for severe hepatic disease by evaluating for cirrhosis, fibrosis, and steatosis without the need for a liver biopsy [27]. Given the increased risk of anemia and hepatic dysfunction, there should be regular monitoring of hemoglobin, iron, erythrocyte protoporphyrin levels, as well as liver function [8, 18]. For patients with EPP who have symptoms of iron deficiency anemia and/or have hemoglobin less than 10 g/dL and ferritin less than 10 μg/L, supplemental iron may be considered [19]. Patients with protoporphyria are also at increased risk of vitamin D deficiency because of sun avoidance; vitamin D supplementation and routine screening for vitamin D deficiency are advised [19].

X-Linked Protoporphyria

Pathobiology

X-linked protoporphyria is a non-blistering cutaneous porphyria caused by gain-of-function mutations in the erythroid-specific 5-aminolevulinate synthase 2 (ALAS2) gene, which encodes the first and rate-limiting enzyme of the erythroid heme biosynthesis pathway [28, 29]. Increased activity of ALAS2 results in excessive production of early heme precursors such as PPIX, exceeding the downstream capacity of FECH [5]. While FECH is functionally normal in XLP, the disproportionate flux through the pathway causes FECH to be functionally rate limiting [30]. Consequently, large quantities of metal-free PPIX accumulate in erythrocytes and plasma, as well as in cutaneous and hepatic tissues [12, 18]. Although the production of PPIX exceeds FECH’s enzymatic capacity, the proportion of metal-free protoporphyrins is lower compared with EPP [19, 28].

Inheritance and Epidemiology

X-linked protoporphyria is inherited in an X-linked dominant pattern and characterized in male individuals by non-blistering photosensitivity, while heterozygous female individuals show variable expressivity depending on the pattern of X-chromosome inactivation within erythroid progenitors [31, 32]. A large North American cohort study found that male patients with XLP had a mean age of symptom onset of 2.7 years compared with 4.1 years in EPP, suggesting an earlier symptom onset compared with EPP [18].

Clinical Features

X-linked protoporphyria and EPP share overlapping phototoxic symptoms [33]. As with EPP, XLP typically manifests in early childhood and is characterized by intense burning and itch of sun-exposed skin within minutes of sun exposure [5]. These symptoms can be accompanied by erythema and swelling and often affect the dorsal hands [7]. Over time, repeated acute photosensitive episodes may result in lichenification and loss of nail lunulae [7, 32]. X-linked protoporphyria is also associated with systemic complications, including anemia and dysregulated iron metabolism, with anemia reported in 30% of male patients with XLP and 75% of female patients with XLP [18]. Additionally, patients with XLP are at increased risk of protoporphyric liver disease, though this risk may be lower than in EPP [30]. One study found that 22.1% of patients with EPP had gallstones, while 40% of male patients with XLP and 33.3% of female patients with XLP had gallstones [18].

Diagnosis

Diagnosis of XLP relies on markedly elevated total erythrocyte protoporphyrins [19]. However, XLP is distinguished by a lower metal-free proportion that is typically 50–85%, compared with 85–100% in EPP [12, 19]. Genetic testing of the ALAS2 gene helps confirm XLP, identifying asymptomatic or variably symptomatic female carriers and distinguishing XLP from EPP [19, 28].

Treatment and Management

Treatment and management of XLP are similar to EPP, with a focus on reducing phototoxic and hepatic injury.

Congenital Erythropoietic Porphyria (CEP)

Pathobiology

Congenital erythropoietic porphyria, also known as Günther disease, is a rare blistering cutaneous porphyria caused by a deficiency of UROS [7]. This is the fourth enzyme in the heme biosynthesis pathway, which converts hydroxymethylbilane to uroporphyrinogen III [11]. When UROS activity is reduced in CEP, cyclization of hydroxymethylbilane leads to uroporphyrinogen I accumulation, resulting in coproporphyrinogen I following the decarboxylation of uroporphyrinogen [34, 35]. These non-physiologic isomers accumulate in erythroid precursors, undergo auto-oxidation to coproporphyrin I and uroporphyrin I, and deposit in erythrocytes and skin [35, 36]. These porphyrins are highly photoactive, generating reactive oxygen species that damage tissues and vascular structures, producing the characteristic blistering and skin fragility in CEP [7].

Inheritance and Epidemiology

Congenital erythropoietic porphyria is inherited in an autosomal recessive pattern with two pathogenic variants of UROS [37]. Previous studies have also reported a GATA1 pathogenic variant, which alters the binding of GATA1 to UROS, on the X chromosome in one patient [38]. Congenital erythropoietic porphyria is an extremely rare disorder, with approximately 220 cases reported worldwide [35].

Clinical Features

The phenotypic spectrum of CEP ranges from non-immune hydrops fetalis to late-onset disease manifesting as mild photosensitivity [37, 39]. Congenital erythropoietic porphyria typically presents at birth or in infancy with blistering and skin fragility of sun-exposed skin, which can lead to infection, scarring, hypertrichosis, and photomutilation of the digits and face [7, 35]. Because of the accumulation of porphyrins, patients may present with red discoloration of urine, erythrodontia, corneal ulcers, and hemolytic anemia, which can progress to chronic hemolytic anemia associated with splenomegaly [7, 38].

Diagnosis

Diagnosis of CEP relies on biochemical testing for elevated uroporphyrins and coproporphyrins in the urine, plasma, and erythrocytes, with coproporphyrins being elevated in the stool [7, 35]. Genetic testing for UROS pathogenic variants confirms the diagnosis of CEP and facilitates family counseling [37].

Treatment and Management

Treatment and management of CEP involves photoprotection and sun avoidance, control of hemolysis, and prevention of organ damage. Patients with CEP require avoidance of sunlight through protective clothing and environmental modifications that prevent exposure to sunlight [11]. With significant hemolysis, blood transfusions may be necessary, which help suppress erythropoiesis and decrease porphyrin production [34]. Additionally, a phlebotomy has been shown to decrease porphyrins in erythrocytes for patients with CEP by inducing mild iron deficiency, thereby limiting iron-dependent ALAS2 translation; iron chelators may also decrease porphyrin levels and improve photosensitivity and hemolysis [40, 41]. Bone marrow transplantation offers a curative approach to CEP for those with severe cutaneous and hematologic involvement or transfusion dependence by eliminating the defective erythroid lineage responsible for excess porphyrin production [37, 42]. Further, ciclopirox shows promise for CEP by stabilizing UROS in a mouse model of CEP, and its efficacy is currently being evaluated in a clinical trial [43, 44]. Because of the increased risk of hemolysis and hepatic dysfunction, regular monitoring of hemoglobin, reticulocytes, iron, bilirubin, along with liver function, is recommended [35]. For those with transfusion dependence, regular monitoring of the iron profile may be done to evaluate for iron overload [34, 35].

Porphyria Cutanea Tarda (PCT)

Pathobiology

Porphyria cutanea tarda is the most common type of porphyria worldwide, with a prevalence of approximately 1:10,000 in Norway and 1:25,000 in the USA [45, 46]. As a blistering cutaneous porphyria, PCT is caused by a deficiency of UROD, which is the fifth enzyme in the heme biosynthesis pathway, which converts uroporphyrinogen III to coproporphyrinogen III [7, 11]. When UROD activity is decreased, uroporphyrinogens are oxidized to uroporphyrins and heptacarboxyl porphyrins, accumulating in the skin and liver [46].

Porphyria cutanea tarda is broadly divided into sporadic and familial forms, which are type I and type II, respectively [47]. Type I PCT is the most common form, involving approximately 80% of cases [46]. This form arises from acquired hepatic inhibition of UROD without germline mutation, restricting enzyme deficiency to hepatocytes only, while erythrocyte UROD activity will be normal [48]. This inhibition results from the increase of hepatic iron and formation of reactive oxygen species from susceptibility factors such as smoking, alcohol use, estrogen use, HIV, hepatitis C, hemochromatosis, and/or iron overload [48, 49]. In contrast, type II PCT is inherited in an autosomal dominant pattern, caused by heterozygous pathogenic variants in UROD [50]. However, as enzymatic activity is reduced by 50%, and 20% is needed for physiologic function, clinical disease manifests only when there are additionally environmental or metabolic triggers, including the aforementioned susceptibility factors [49, 50]. Patients with PCT have clinical disease when there is the presence of at least two susceptibility factors, which also includes pathogenic variants in UROD [46, 51].

Clinical Features

The accumulated photoactive porphyrins in PCT create a painful blistering photosensitivity and skin fragility following exposure to sunlight [7]. The most affected areas include the dorsal hands, forearms, and face, with repeated sun exposure causing scarring and hypertrichosis [7] (Fig. 3). Additionally, the cutaneous manifestations of PCT are clinically identical to VP, HCP, and late-onset of CEP [5]. While PCT is primarily a cutaneous disorder, long-term complications of PCT can include liver cirrhosis and hepatocellular carcinoma (HCC), given the persistent accumulation of porphyrins in the liver [52].

Fig. 3.

Erythematous plaques, erosions, and bullae affecting the dorsal hands of a patient with porphyria cutanea tarda. Clinical photograph courtesy of Horner et al. [53]

Diagnosis

Diagnosis of PCT focuses on biochemical testing of elevated plasma and urine porphyrins, with a characteristic predominance of uroporphyrin and heptacarboxyl porphyrin [53]. Although a skin biopsy can help rule out other skin conditions, it cannot provide the diagnosis of PCT, given that other cutaneous lesions are histologically similar to PCT such as pseudoporphyria [46, 54]. The histologic findings in PCT typically demonstrate subepidermal blistering, dermal papillae festooning, and thickening of the basement membrane and dermal blood vessel walls [54]. These features are not specific to PCT, as they may be seen in pseudoporphyria syndromes as well [54]. Pseudoporphyria is a photo-distributed bullous skin disorder that clinically and histologically mimics PCT, but this condition occurs without abnormalities in porphyrin metabolism [46]. The associated causes of pseudoporphyria include nonsteroidal anti-inflammatory drugs, retinoids, antibiotics, diuretics, as well as chronic kidney disease, while management focuses on removing and treating the underlying cause [46]. Distinguishing pseudoporphyria from PCT therefore relies on porphyrin studies, as porphyrin levels remain normal in pseudoporphyria [46]. Accurate diagnosis of PCT is supported by characteristic patterns of porphyrin accumulation [7]. In situations where familial disease is suspected, genetic testing for UROD mutations can help differentiate PCT from VP, HCP, and late-onset CEP [11, 53].

Treatment and Management

Treatment and management of PCT include correcting the biochemical defect by reducing hepatic iron and decreasing hepatic porphyrin production, as well as identifying and mitigating susceptibility factors such as smoking, alcohol consumption, estrogen use, HIV infection, hepatitis C infection, hemochromatosis, and iron overload. Phlebotomy is a mainstay therapy for PCT, as removal of excess iron restores hepatic UROD activity, leading to decreased serum porphyrins and subsequent biochemical and clinical remission [46, 55]. Monitoring serum ferritin levels can assess for relapse following phlebotomy therapy [56]. Low-dose hydroxychloroquine can also effectively treat PCT by inhibiting the production and secretion of porphyrins, though this is contraindicated in pregnancy, liver and retinal disease, and hepatotoxic drug usage [46, 57]. In patients with PCT and hepatitis C, PCT can be effectively treated with direct-acting antiviral drugs against hepatitis C, such as ledipasvir/sofosbuvir [58]. The use of these drugs has led to a marked decline in hepatitis C-associated PCT [58]. Monitoring of urine and plasma porphyrins is advised to evaluate for recurrence [46].

Hepatoerythropoietic Porphyria (HEP)

Pathobiology

Hepatoerythropoietic porphyria is an exceptionally rare cutaneous porphyria that is caused by a deficiency of UROD [7]. Hepatoerythropoietic porphyria is the autosomal recessive form of familial PCT, with biallelic pathogenic variants in the UROD gene resulting in drastically low UROD enzyme activity (<10%) [59]. Thus, HEP represents a more severe form of familial PCT and is distinguished by early childhood onset [60, 61]. The impairment of UROD leads to the oxidation of uroporphyrinogens to uroporphyrins and heptacarboxyl porphyrins, which accumulate in the skin and liver [62].

Inheritance and Epidemiology

Hepatoerythropoietic porphyria is inherited in an autosomal recessive pattern, with less than 100 cases of HEP reported [62]. Affected individuals have homozygosity or compound heterozygosity for UROD mutations [63, 64]. Consistent with this genetic heterogeneity, UROD molecular diagnostic testing over an 11-year period identified a novel mutation in one of four unrelated patients with HEP, highlighting the allelic diversity of HEP [63].

Clinical Features

Clinically, HEP typically presents in infancy or early childhood with severe blistering photosensitivity, often before 2 years of age [7]. Children may also develop skin fragility, scarring, hypertrichosis, and photomutilation [7, 65]. The accumulation of porphyrins also leads to red urine and ocular damage, with rarer manifestations including erythrodontia and hemolytic anemia, which often results in chronic hematologic abnormalities and splenomegaly [5, 62]. The clinical manifestations of HEP resemble PCT but are more severe, with PCT typically affecting middle-aged patients [50, 59]. Hepatic damage can occur in HEP when porphyrins accumulate in the liver and are secreted into the bile, though no increased risk for HCC has been reported [59, 62].

Diagnosis

Diagnosis of HEP relies on biochemical testing of elevated total porphyrins in the urine or plasma, with increased uroporphyrins and heptacarboxyl porphyrins [62, 66]. The clinical manifestations of HEP are also similar to CEP, and elevated erythrocyte zinc protoporphyrin levels in HEP can help distinguish the disorder from CEP and PCT as well [48, 62]. Genetic testing for biallelic pathogenic variants in UROD confirms the diagnosis [67].

Treatment and Management

Treatment and management of HEP includes photoprotection and sun avoidance, along with avoidance of susceptibility factors in PCT such as smoking, alcohol use, estrogen use, HIV, hepatitis C, hemochromatosis, and iron overload [5, 62]. Monitoring urine and plasma porphyrins over time may be reasonable [62]. While phlebotomy and hydroxychloroquine are effective therapies for PCT, these are not effective for HEP [5]. Although previous experimental studies have long suggested HEP as a potential candidate for gene-based therapies, this rationale has not been translated into clinical gene therapy trials [68].

Acute Hepatic Porphyrias (AHPs)

Acute Intermittent Porphyria (AIP)

Pathobiology

Acute intermittent porphyria is an AHP caused by a partial deficiency in porphobilinogen deaminase, also known as hydroxymethylbilane synthase (HMBS), the third enzyme of heme biosynthesis [1]. This enzymatic deficiency impairs the conversion of PBG to hydroxymethylbilane, leading to the accumulation of PBG and its precursor ALA, which results in the neurovisceral presentations of AIP [69]. In this setting, precipitating factors, including infections, caloric restriction with fasting and dieting, alcohol and tobacco use, hormonal fluctuations, and exposure to porphyrinogenic medications such as certain anticonvulsants and antibiotics, lead to upregulation of hepatic δ-aminolevulinate synthase 1 (ALAS1) [4, 70–72]. This exacerbates the accumulation of ALA and PBG, resulting in acute attacks, as demand for heme exceeds the capacity of downstream enzymes such as HMBS. Given that ALA is a non-photoactive non-fluorescent porphyrin precursor affecting the autonomic, peripheral, and central nervous systems, AIP is characterized by autonomic and neurologic instability rather than photosensitivity [73].

Inheritance and Epidemiology

Acute intermittent porphyria is the most common AHP and is inherited in an autosomal dominant pattern with low penetrance, resulting from pathogenic variants in the HMBS gene [4]. More than 400 HMBS mutations have been documented, and genetic analyses have found that the prevalence of these mutations is 1:1675 [74, 75]. Founder mutations have also been reported in certain populations such as Sweden, contributing to regionally elevated prevalence [76].

Clinical Features

The clinical presentation of AIP is predominantly acute neurovisceral attacks, which typically begin with diffuse severe abdominal pain [1]. Patients often develop nausea, vomiting, constipation, tachycardia, and hypertension, as well as neurologic manifestations such as limb pain, weakness, or central nervous system dysfunction [77, 78] (Table 2). Neuropsychiatric symptoms can also occur in AIP cases, such as anxiety, agitation, hallucinations, or confusion, especially during prolonged or untreated acute attacks [77, 78]. Hyponatremia is a common electrolyte abnormality during acute attacks, increasing the risk for seizures [78]. Notably, AIP does not affect the skin, and therefore, the overall lack of skin involvement should not preclude consideration of the diagnosis [78]. Long-term complications of AIP include chronic kidney disease and chronic hypertension, with studies reporting porphyria-associated kidney disease and concomitant hypertension in approximately 60% of patients with AIP [79]. Patients with AIP are also at higher risk of liver disease and HCC [4].

Table 2.

Summary of key characteristics, diagnosis, and management of acute hepatic porphyrias

Porphyria	Inheritance	Gene (defected enzyme)	Key accumulated metabolites	Key clinical symptoms and features	Diagnosis	Treatment and management	Long-term monitoring
Acute hepatic porphyrias
Acute intermittent porphyria	Autosomal dominant [4]	HMBS (porphobilinogen deaminase/hydroxymethylbilane synthase) [1]	ALA, PBG [69]	Acute neurovisceral attacks with abdominal pain, nausea, vomiting, constipation, tachycardia, hypertension, limb pain, weakness, central nervous dysfunction [77, 78]; neuropsychiatric symptoms such as anxiety, agitation, hallucinations, and confusion [77, 78]; risk of seizures because of hyponatremia [78]	Elevated urine ALA and PBG levels during acute attacks [4]; confirmation with genetic testing of HMBS [4]	Hemin [82, 83]; dextrose, analgesia, antiemetics, electrolyte correction [4, 11]; identification and removal of triggers [81]; givosiran [87]; GnRH analogs [88]; liver transplantation in refractory cases [4]	Renal function, liver function, HCC surveillance with a liver ultrasound [4, 79]
Variegate porphyria	Autosomal dominant [89]	PPOX (protoporphyrinogen oxidase) [89]	ALA, PBG, photoactive protoporphyrin, coproporphyrin III [4, 89]	Acute neurovisceral attacks with abdominal and limb pain, nausea, vomiting, constipation, tachycardia, and hypertension [77, 78]; neuropsychiatric symptoms such as agitation, hallucinations, and confusion [77, 78]; blistering photosensitivity and skin fragility [7, 89]	Elevated urine ALA and PBG levels during acute attacks [4, 80]; elevated plasma and fecal porphyrins (particularly stool protoporphyrin and coproporphyrin III) [80]; plasma fluorescence scanning with emission peak at around 626 nm [5]; confirmation with genetic sequencing of PPOX [4]	Photoprotection and sun avoidance [7, 11]; hemin, dextrose [11, 82, 84]; analgesia, antiemetics, electrolyte correction [4, 11]; identification and removal of triggers [81]; givosiran [87]; GnRH analogs [88]; liver transplantation in refractory cases [4, 93]	Renal function, liver function, HCC surveillance with a liver ultrasound [4]
Hereditary coproporphyria	Autosomal dominant [96]	CPOX (coproporphyrinogen oxidase) [11, 96]	ALA, PBG, photoactive coproporphyrin III [4, 96]	Acute neurovisceral attacks with abdominal pain, nausea, vomiting, constipation, tachycardia, hypertension, limb pain, motor neuropathy, and seizures [77, 78, 96]; neuropsychiatric symptoms such as anxiety, agitation, hallucinations, and confusion [77, 78]; blistering photosensitivity and skin fragility [7]	Elevated urine PBG and ALA levels during acute attacks [4]; increased coproporphyrin III on fecal porphyrin analysis (with an elevated coproporphyrin III:I ratio and 60–95% of the total coproporphyrin being coproporphyrin III) [89, 96]; confirmation with genetic testing of CPOX [4]	Photoprotection and sun avoidance [7]; hemin [82, 84]; dextrose [11, 81]; analgesia, antiemetics, electrolyte correction [4, 11]; identification and removal of triggers [81]; givosiran [87]; GnRH analogs [88]; liver transplantation in refractory cases [4]	Renal function, liver function, HCC surveillance with a liver ultrasound [4]
Aminolevulinic acid dehydratase deficiency porphyria	Autosomal recessive [101]	ALAD (aminolevulinic acid dehydratase) [100]	ALA [4]	Acute neurovisceral attacks with abdominal pain, nausea, vomiting, and constipation [77, 78]; severe, recurrent neurological attacks [100]; neuropsychiatric symptoms such as sensory and motor neuropathy, agitation, hallucinations, and depression [77, 78]; childhood onset with a male sex predominance [4]	Elevated urine ALA in the absence of elevated PBG [4, 100]; confirmation with genetic testing of ALAD [4, 5]	Hemin, dextrose [81, 82, 84]; analgesia, antiemetics, electrolyte correction [4, 11]; identification and removal of triggers [81, 100]; liver transplantation in refractory cases [4, 100]	Renal function, liver function, HCC surveillance with a liver ultrasound [4]

ALA δ-aminolevulinic acid, GnRH gonadotropin-releasing hormone, HCC hepatocellular carcinoma, PBG porphobilinogen

Diagnosis

Diagnosis of AIP relies on an elevated presence of ALA and PBG in a spot urine sample during acute attacks [4]. These urine ALA and PBG levels can remain elevated for months to years following an acute attack [4]. Testing with spot urine is highly sensitive, as urine PBG levels are at least five-fold above normal during acute attacks [4, 80, 81]. Following positive biochemical testing, genetic testing of HMBS is recommended for confirmatory diagnosis and family screening, particularly because mutation carriers can remain asymptomatic [4].

Treatment and Management

Treatment and management include agents targeted to suppression of ALAS1 activity, removal of precipitating factors, and supportive care. For acute attacks, intravenous hemin is used to provide negative feedback on hepatic heme synthesis and reduce the production of ALA and PBG [82, 83]. Hemin is an iron-containing porphyrin that repletes the hepatic heme pool, downregulating ALAS1 [82–84]. Consequently, the production of ALA and PBG is reduced as well. Intravenous dextrose can also be used to suppress ALAS1 activity in milder attacks, and in certain regions, it may be more commonly used for acute attacks because of the limited availability or high cost of intravenous hemin [11, 85]. Supportive care often includes analgesia for pain, antiemetics for nausea and vomiting, and correction of electrolyte abnormalities such as hyponatremia [4, 11]. Identification and elimination of triggers, such as porphyrinogenic medications, fasting, dieting, infections, and alcohol and tobacco use, are central to the acute management and prevention of future attacks [81]. For those with recurrent attacks, off-label use of prophylactic hemin therapy or small interfering RNA-based therapy targeting ALAS1 with givosiran may be considered to reduce attack frequency and hospitalizations [86, 87]. However, prophylactic hemin therapy has not been definitively proven to be effective in preventing recurrent attacks [4]. Givosiran has been approved by the US Food and Drug Administration to treat adults with AHP and demonstrated a 74% decrease in the annualized attack rate when compared with placebo in a phase III clinical trial [87]. However, its use may be limited because of the high cost, with an average annual cost of $575,000 [85]. Liver enzymes, renal function, amylase, lipase, and homocysteine should be monitored after initiating givosiran therapy [11]. Gonadotropin-releasing hormone (GnRH) analogs may also be used to manage attacks related to menstrual cycles and hormonal changes [88]. The curative treatment for AIP and other AHPs is liver transplantation; however, this is generally reserved for those unresponsive to pharmacologic therapy [4]. Long-term monitoring for disease-related complications, particularly renal and hepatic sequelae, is essential given the systemic consequences of recurrent porphyrin precursor accumulation. As chronic kidney disease is a well-documented complication of AIP, regular assessment of renal function is recommended [4, 79]. Liver function testing and HCC surveillance with a liver ultrasound every 6 months, beginning at age 50 years, are also advised because of the higher risk of hepatic malignancy [4].

Variegate Porphyria (VP)

Pathobiology

Variegate porphyria is an AHP caused by a partial deficiency of PPOX [89]. This enzymatic deficiency impairs the conversion of protoporphyrinogen IX to PPIX [90]. Upstream protoporphyrinogens and porphyrin precursors accumulate in the liver and circulation when PPOX activity is reduced [89]. These intermediates, notably ALA, PBG, and photoactive protoporphyrin and coproporphyrin III, contribute to the clinical manifestations of VP [4, 89]. δ-Aminolevulinic acid and PBG result in disturbances in the autonomic, peripheral, and central nervous systems, underlying the acute neurovisceral attacks in VP and other AHPs [4]. Additionally, in VP, photoactive porphyrins in circulation accumulate in the skin and lead to photosensitivity due to the generation of reactive oxygen species following visible light exposure [7, 89]. This photosensitivity results in blistering skin lesions upon sun exposure, which are identical to other blistering cutaneous porphyrias such as PCT [7]. This chronic blistering photosensitivity is often localized to the dorsal hands, creating subepidermal blisters that may rupture and become infected, a distribution and morphology similar to PCT [89]. In contrast to PCT, however, cutaneous manifestations in VP occur in the setting of AHP and may be accompanied by neurovisceral symptoms, although patients may also present with isolated cutaneous manifestations [89].

Inheritance and Epidemiology

Variegate porphyria results from pathogenic variants in the PPOX gene, following an autosomal dominant inheritance pattern with reduced penetrance [89]. While VP is rare worldwide, with a prevalence of approximately 0.3:100,000, its prevalence varies by region [91]. In South Africa, where VP is relatively common, founder variants highlight certain regions with higher rates of disease [92].

Clinical Features

Variegate porphyria is notable for both acute neurovisceral symptoms and cutaneous photosensitivity [89]. Acute attacks are typically characterized by severe abdominal and limb pain, along with nausea, vomiting, tachycardia, hypertension, and constipation [77, 78]. Neuropsychiatric manifestations, including hallucinations, agitation, and confusion, may occur as well [77, 78]. In addition to these acute attacks, patients can experience cutaneous manifestations in photo-exposed areas. Following ultraviolet A and visible light exposure, the skin may become fragile and develop blisters, erosions, and scarring [7, 89] (Fig. 4). Over time, recurrent photodamage may result in pigmentary changes and chronic skin fragility [7]. Long-term complications of VP include chronic pain, blistering photosensitivity, scarring, and skin fragility related to cutaneous involvement, hypertension, and both hepatic and renal disease [77, 89]. The cumulative toxic effects of circulating ALA and PBG increase the risk of HCC and chronic kidney disease in patients with VP, particularly those over the age of 50 years [4].

Fig. 4.

Early blistering and crusting affecting the right dorsal hand (white arrow) in a photo-exposed distribution of a patient with variegate porphyria. Clinical photograph courtesy of Fatima et al. [102]

Diagnosis

Diagnosis of VP includes biochemical testing and genetic analysis. During an acute attack, elevated urine ALA and PBG levels suggest an AHP, and these levels may normalize between attacks in VP [4, 80]. In VP, urine PBG may be more transiently elevated when compared with AIP [11]. Urine, plasma, and fecal porphyrin profiles, particularly stool protoporphyrin and coproporphyrin III, are informative in VP and can be used as second-line testing following a positive or inconclusive AHP test [80]. Plasma fluorescence scanning can provide additional diagnostic support, even in the absence of symptoms, as VP has a characteristic emission peak at around 626 nm [5]. Genetic sequencing of PPOX can identify pathogenic variants in the gene, confirming diagnosis and facilitating family screening [4].

Treatment and Management

Treatment and management of VP include prompt treatment of acute attacks, prevention of triggering factors, photoprotection, and sun avoidance. Acute neurovisceral attacks in VP are also treated with intravenous hemin, and in milder attacks, intravenous dextrose can provide temporary symptomatic benefit [11, 82, 84]. Supportive care encompasses pain control, antiemetic therapy, and correction of electrolyte abnormalities, particularly hyponatremia [4, 11]. Preventative management is the identification and avoidance of precipitating factors such as porphyrinogenic medications, fasting, dieting, substance use, and infections [81]. Although off-label prophylactic intravenous hemin is widely used and can effectively abort acute attacks in VP and other AHPs, its role in preventing recurrent attacks remains less well established [4]. Patients receiving long-term hemin therapy should be monitored for complications such as iron overload and catheter-associated complications [11]. Givosiran can also be considered to reduce the frequency of attacks [87]. Gonadotropin-releasing hormone analogs may also be used to manage attacks triggered by menstrual cycles and hormonal fluctuations [88]. While liver transplantation remains the curative treatment for VP and other AHPs, this is considered for patients unresponsive to pharmacologic therapy [4, 93]. Cutaneous symptoms in VP are typically managed through sun avoidance and photoprotection with protective clothing and sunscreens that filter visible light, as there are currently no therapies approved to treat the blistering photosensitivity [7, 11]. However, emerging evidence suggests a potential role for afamelanotide, a synthetic α-melanocyte stimulating hormone agonist that increases eumelanin production and enhances photoprotection [94]. A phase IIa study (NCT05854784) demonstrated improvements in disease severity and quality of life among patients with VP treated with afamelanotide [94]. Afamelanotide has received orphan drug designation in Europe for this indication (EU/3/24/2947) [95]. These findings suggest a promising therapeutic option for patients with VP experiencing cutaneous disease. Additionally, because AHPs, including VP, carry increased risks of kidney and liver disease, VP requires long-term monitoring of liver and renal function and HCC surveillance with a liver ultrasound every 6 months starting at 50 years of age [4].

Hereditary Coproporphyria (HCP)

Pathobiology

Hereditary coproporphyria is an AHP caused by a partial deficiency of CPOX, the sixth enzyme in the heme biosynthesis pathway that converts coproporphyrinogen III to protoporphyrinogen IX [11, 96]. With a deficiency of CPOX, coproporphyrinogen III accumulates in hepatocytes and auto-oxidizes to coproporphyrin III, which is then excreted in urine and stool [97]. Upregulation of ALAS1 leads to increased production of ALA and PBG, driving the acute neurovisceral attacks characteristic of HCP [4, 96]. Compared to VP, the blistering photosensitivity symptoms of HCP are similar but less frequent, as photoactive porphyrin accumulation in the skin may be less extensive [7]. One analysis involving 46 patients with HCP found that only 13% had cutaneous symptoms [98].

Inheritance and Epidemiology

Hereditary coproporphyria is inherited in an autosomal dominant pattern, caused by pathogenic variants in the CPOX gene [96]. Among AIP, VP, and HCP, HCP is the least prevalent, with a nationwide cohort study reporting an estimated prevalence of approximately 2.9 per million for HCP in Israel [99].

Clinical Features

Hereditary coproporphyria clinically resembles AIP and VP, with acute attacks presenting with abdominal pain, nausea, vomiting, constipation, tachycardia, and hypertension [77, 78]. When compared with AIP, acute attacks of HCP are rare, and it is likely that only a small number of CPOX heterozygotes develop clinical manifestations [96]. Further, neurologic manifestations may include limb pain, motor neuropathy, and seizures during acute attacks [77, 78, 96]. Neuropsychiatric symptoms can also include anxiety, agitation, confusion, and hallucinations [77, 78]. The cutaneous involvement in HCP resembles that of VP, including skin fragility, blistering, and scarring in sun-exposed areas of the skin [7]. However, these symptoms are less common than in VP [7]. Long-term complications of HCP may include chronic pain, blistering photosensitivity, scarring, skin fragility, hypertension, and as with other AHPs, there is an increased risk of HCC and chronic kidney disease in HCP [4, 77, 96].

Diagnosis

Diagnosis of HCP includes assessing urine PBG and ALA levels during acute attacks [4]. A fecal porphyrin analysis often shows increased coproporphyrin III, with an elevated coproporphyrin III:I ratio and 60–95% of the total coproporphyrin being coproporphyrin III [89, 96]. As mutation carriers may not develop symptoms, genetic testing of CPOX allows for diagnostic confirmation and enables family screening [4].

Treatment and Management

Similar to other AHPs, treatment and management of HCP focus on suppression of ALAS1, removal of precipitating factors, and supportive care. Intravenous hemin remains the most effective therapy for acute attacks, reducing the production of neurotoxic ALA and PBG [82, 84]. Carbohydrate loading with intravenous dextrose can also be used in mild attacks [11, 81]. Supportive treatment often includes analgesia, antiemetics, and correction of electrolyte abnormalities such as hyponatremia [4, 11]. Preventing future attacks requires identification and elimination of triggers such as porphyrinogenic medications, fasting, dieting, infections, and alcohol and tobacco use [81]. Off-label use of prophylactic intravenous hemin can treat acute attacks; however, while it may be considered in patients experiencing recurrent attacks, its effectiveness in preventing them remains unclear, and long-term use carries risks of iron overload and catheter-associated complications [4]. Small interfering RNA-based therapy targeting ALAS1 with givosiran can also be used to reduce attack frequency [87]. Gonadotropin-releasing hormone analogs can help manage attacks associated with menstrual cycles and hormonal changes [88]. Although the curative treatment for HCP and other AHPs is liver transplantation, it is typically considered only when pharmacologic therapy fails [4]. When cutaneous symptoms are present, management with photoprotection and sun avoidance is similar to VP [7]. Regular monitoring of liver and renal function is advised, and surveillance of HCC with a liver ultrasound every 6 months starting at age 50 years is also recommended, as HCP shares the increased hepatic cancer risk seen in other AHPs [4].

Aminolevulinic Acid Dehydratase Deficiency Porphyria (ADP)

Pathobiology

Aminolevulinic acid dehydratase deficiency porphyria is an exceedingly rare AHP caused by the deficiency of ALAD, which is the second enzyme of the heme biosynthesis pathway that catalyzes the condensation of two ALA molecules to produce PBG [100]. Caused by biallelic pathogenic variants in the ALAD gene, ADP is an autosomal recessive disorder with fewer than ten cases reported [101]. As ALAD activity is reduced, ALA accumulates to high levels, exerting neurotoxicity on the autonomic, peripheral, and central nervous systems [4]. While the clinical presentation is similar to other AHPs, ADP is distinguished biochemically by the lack of elevated PBG levels [4, 100]. Aminolevulinic acid dehydratase is particularly known to be sensitive to inhibitors; therefore, exogenous exposures to heavy metals such as lead can further impair ALAD by displacing zinc ions [2, 100].

Clinical Features

The acute neurovisceral symptoms of ADP are similar to those of other AHPs, including abdominal pain, nausea, vomiting, and constipation [77, 78]. However, ADP has a typical age of onset in childhood with a male sex predominance [4]. Aminolevulinic acid dehydratase deficiency porphyria is also characterized by more severe symptoms, including life-threatening recurrent neurological attacks [100]. Given the accumulation of ALA, the neurologic and psychiatric features of other AHPs can be seen in ADP as well, such as sensory and motor neuropathy, agitation, hallucinations, and depression [77, 78]. Long-term complications also include persistent neuropathy, motor weakness, dysarthria, and both hepatic and renal disease [4, 78, 100].

Diagnosis

Diagnosis of ADP requires markedly elevated urine ALA in the absence of elevated PBG, in contrast to other AHPs where PBG remains elevated during acute attacks [4, 100]. As ADP is very rare, a high index of suspicion is needed for diagnosis [100]. Genetic testing of the ALAD gene provides patients with diagnostic confirmation and can help differentiate hereditary ADP from acquired ADP [4, 5].

Treatment and Management

Management of ADP parallels treatments for other AHPs, though evidence is limited owing to a small number of documented cases. Intravenous hemin remains the primary therapy for acute attacks, while carbohydrate loading with intravenous dextrose may provide symptomatic relief in milder attacks [81, 82, 84]. Supportive measures, such as pain control, antiemetic therapy, and monitoring and correction of electrolytes, are essential [4, 11]. Identification and avoidance of precipitating factors prevents future attacks, which includes porphyrinogenic medications, fasting, dieting, substance use, infections, and heavy metals, particularly lead [81, 100]. The curative treatment is liver transplantation, which is considered for patients who do not respond to pharmacologic therapy, though studies have reported treatment failure with liver transplant in ADP [4, 100]. As with other AHPs, patients with ADP should regularly undergo hepatic and renal function monitoring, as well as HCC surveillance [4].

Conclusions

Cutaneous porphyrias, along with AHPs, comprise a diverse group of disorders in which variable biochemical disruptions give rise to broad clinical manifestations, challenging timely and accurate diagnosis. This review article highlights the heterogeneity across porphyria subtypes in pathobiology, presentation, and disease course, emphasizing clinical patterns and appropriate evaluation and management. Advancing clinician awareness of porphyrias, along with continued research into underlying mechanisms and therapeutic strategies, enables timely diagnosis, optimal management, and improved patient outcomes. Recent breakthroughs in management have allowed for viable treatment options and should help attract patients to seek care.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Funding

No funding was received for the preparation of this article.

Conflict of Interest

Stanislav N. Tolkachjov is an investigator/speaker for Bioventus, Kerecis, Boehringer Ingelheim, Regeneron, Leo Pharma, and CASTLE. Tasneem F. Mohammad is an investigator for Mitusishi Tanabe, Clinuvel, and Disc Medicine and has served on an advisory board for Disc Medicine. Ivo Abraham is the Quantitative Methods Editor of JAMA Dermatology, which is a compensated editorship contracted to Matrix45. He is the Editor-in-Chief of the Journal of Medical Economics, which is an uncompensated editorship but for which he receives an annual allotment of submissions free of publication charges. Daniel Grove is a consultant for Disc Medicine and has served on their advisory committees. Toan N. Vu, Sahithi Talasila, George M. Jeha, Umer Nadir, and Henry W. Lim have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

Institutional review board approval was not required because this study is a review of previously published literature and does not involve human participants or identifiable patient data.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Data availability is not applicable, as no new data were created or analyzed in this study.

Code Availability

Not applicable.

Authors’ Contributions

Conceptualization: TNV, ST, UN; methodology: TNV, ST; formal analysis and investigation: TNV; writing (original draft preparation): TNV; writing (review and editing): TNV, ST, GMJ, UN, TFM, HWL, IA, DG, SNT; supervision: SNT. All authors have read and approved the final version.