2025 日本临床实践指南：卟啉症的管理（英文版）

ABSTRACT

Porphyrias are rare metabolic disorders caused by decreased or increased activity of one of the nine enzymes involved in the heme biosynthetic pathway, resulting in the accumulation of porphyrias or their precursors. Although nine subtypes are currently recognized, substantial overlap in clinical manifestations often makes diagnosis challenging. This article presents the English version of the first national clinical practice guidelines for porphyrias in Japan, originally published in 2025 by the Japanese Dermatological Association. The guidelines were developed by the Clinical Practice Guideline Committee, established as part of the Research Project on Intractable Diseases of the Ministry of Health, Labour and Welfare of Japan. Diagnostic and severity assessment criteria were based on those proposed by the Ministry research group. Clinical questions (CQs) were formulated, and recommendations were developed according to the principles of evidence-based medicine, incorporating both domestic and international evidence. The guidelines provide diagnostic criteria, severity classification, and evidence-based recommendations for the management of porphyrias. Although causative genes have been identified, the pathophysiology remains incompletely understood, and no curative therapy is currently available, and liver transplantation may be required in severe cases with liver failure. These guidelines aim to provide practical guidance for clinicians managing porphyrias in Japan. Future revisions will be necessary in response to advances in diagnostic technologies and therapeutic strategies.

1 | Guideline Positioning

These guidelines were developed by a committee consisting of members and research collaborators of the Research Project

on Intractable Diseases (fiscal years 2016–2025) supported by the Ministry of Health, Labour and Welfare, together with representatives commissioned by the Japanese Dermatological Association. Beginning in 2023, the committee held meetings

and conducted written deliberations to formulate the recommendations. A public comment process was then undertaken, followed by approval from the Guideline Committee and the Board of Directors of the Japanese Dermatological Association. These guidelines represent the current fundamental and standard recommendations for the clinical management of porphyrias in Japan.

A list of abbreviations is provided in Table 1.

2 | Levels of Evidence and Recommendation Grading

The classification of levels of evidence and recommendation grading in these guidelines was based on the criteria adopted in the Clinical Practice Guidelines for Skin Malignancies, 2nd Edition edited by the Japanese Dermatological Association [1].

TABLE 1 | List of abbreviations.

|Abbreviations|Official name|Abbreviations|Official name| |---|---|---|---| |25(OH)D|25-hydroxyvitamin D|isoCP|Isocoproporphyrin| |7P|Heptacarboxylporphyrin|MDS|Myelodysplastic syndromes| |ADP|Aminolevulinate dehydratase deficiency porphyria|NSAIDs|Nonsteroidal anti-inflammatory drugs| |AIP|Acute intermittent porphyria|PAKD|Porphyrin associated kidney disease| |ALA|δ-aminolevulinic acid|PAS|Periodic acid-Schiff| |ALAD|Aminolevulinate dehydratase|PBG|Porphobilinogen| |ALAS|δ-aminolevulinic acid synthase|PCB|Polychlorinated biphenyl| |ATP|Adenosine triphosphate|PCT|Porphyria cutanea tarda| |CEP|Congenital erythropoietic porphyria|PPF|Photosensitivity protection factor| |CI|Confidence interval|PIPIX|Protoporphyrin| |CKD|Chronic kidney disease|PPOX|Protoporphyrinogen oxidase| |CLPX|Caseinolytic mitochondrial matrix peptidase chaperone subunit X|QOL|Quality of life| |CP|Coproporphyrin|RBC|Red blood cell| |CPOX|Coproporphyrinogen oxidase|RCT|Randomized controlled trial| |CQ|Clinical question|RNA|Ribonucleic acid| |CYP|Cytochrome P450|ROS|Reactive oxygen species| |DNA|Deoxyribonucleic acid|UDCA|Ursodeoxycholic acid| |EPP|Erythropoietic protoporphyria|UL|Tolerable Upper Intake Level| |FAH|Fumarylacetoacetate hydrolase|ULN|Upper limit of normal| |FECH|Ferrochelatase|UP|Uroporphyrin| |GABA|γ-aminobutyric acid|UROD|Uroporphyrinogen decarboxylase| |GATA1|GATA-binding transcription factor 1|UROS|Uroporphyrinogen III synthase| |HCC|Hepatocellular carcinoma|UV|Ultraviolet| |HCP|Hereditary coproporphyria|VP|Variegate porphyria| |HCV|Hepatitis C virus|XLP|X-linked protoporphyria| |HEP|Hepatoerythropoietic porphyria|XP|X-porphyrin| |HMBS|Hydroxymethylbilane synthase|||

2.1 | Levels of Evidence

I. Systematic reviews or meta-analyses of randomized controlled trials (RCTs).

II. At least one RCT.

III. Non-RCTs (including statistically analyzed before-and-after studies).

IV. Analytical epidemiological studies (cohort studies or case-control studies).

V. Descriptive studies (case reports or case series).

VI. Opinions of expert committees or individual experts.

2.2 | Grades of Recommendation

A: Strongly recommended (supported by at least one level I study demonstrating efficacy, or by high-quality level II evidence).

A*: Recommended (evidence of efficacy equivalent to grade A, but downgraded due to considerations such as adverse effects).

B: Recommended (supported by one or more lower-quality level II studies, high-quality level III evidence, or very high-quality level IV evidence).

C1: May be considered as one option (supported by lower-quality level III–IV evidence, multiple high-quality level V studies, or level VI evidence accepted by the committee).

C2: Not recommended at present due to insufficient evidence (no evidence of efficacy or evidence of ineffectiveness).

D: Strongly discouraged (supported by high-quality evidence demonstrating a lack of efficacy or evidence of harm).

3 | Definitions and Concepts

Heme is an essential molecule for maintaining vital biological functions, forming a component of hemoglobin, myoglobin, cytochrome c, cytochrome P450 (CYP), catalase, nitric oxide synthase, and peroxidases. The system responsible for synthesizing heme is referred to as the heme biosynthetic pathway [2]. Since heme synthesis proceeds through porphyrin intermediates, this pathway is also called the porphyrin metabolic pathway. Nine enzymes are involved in this system, with δ-aminolevulinic acid synthase (ALAS) serving as the rate-limiting enzyme that regulates heme production.

Porphyrias represent a group of metabolic disorders of the porphyrin pathway caused by abnormalities in the activity of one of these nine enzymes. Such enzymatic dysfunction leads to decreased heme production accompanied by the excessive biosynthesis and accumulation of porphyrins or their precursors in the body, resulting in diverse pathological symptoms [3, 4]. Depending on which enzyme is affected, porphyrias are currently classified into nine subtypes (Table 2), which are broadly divided into two categories based on clinical manifestations: acute porphyrias, which primarily present with neuropsychiatric and gastrointestinal symptoms, and cutaneous porphyrias, which predominantly present with skin symptoms.

Most enzymatic abnormalities are genetically determined; however, in porphyria cutanea tarda (PCT), acquired factors, such as alcohol consumption or hepatitis C virus (HCV) infection, may also be causative. Acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinate dehydratase deficiency porphyria (ADP). Cutaneous porphyrias include congenital erythropoietic porphyria (CEP), erythropoietic protorphyria (EPP), X-linked protoporphyria (XLP), PCT, and hepatoerythropoietic porphyria (HEP). The main clinical features of porphyrias are cutaneous manifestations, neuropsychiatric symptoms, and gastrointestinal symptoms; however, the extent and combination of these features vary depending on the subtype. In particular, acute porphyrias are characterized by paroxysmal episodes of neuropsychiatric and gastrointestinal symptoms. In addition to the underlying enzymatic defect,

various precipitating factors such as drugs, alcohol consumption, fasting, hormonal changes during menstruation, and physical or mental stress are typically involved in disease onset. Importantly, AIP and ADP do not present with cutaneous manifestations such as photosensitivity.

4 | Diagnostic Criteria and Severity Classification

4.1 | Diagnostic Criteria for Cutaneous Porphyrias

4.1.1 | EPP

1. Clinical Symptoms.

Photosensitivity: During or after sun exposure, patients develop painful erythema and edema on sun-exposed areas. In severe cases, vesicles and erosions may occur.

2. Clinical Findings.

i. Cutaneous manifestations: On sun-exposed areas, erythema, edema, facial pitted scars, hyperpigmentation, lichenification, and hypertrichosis.

ii. Liver dysfunction.

3. Laboratory Findings

i. Markedly elevated erythrocyte protoporphyrin levels (≥3×upper limit of normal [ULN]) [5].

ii. Urinary porphyrin precursors and porphyrins remain within the normal ranges.

iii. Positive erythrocyte fluorescence.

iv. Positive photochemolysis test.

v. Deposition of periodic acid-Schiff (PAS)-positive material around dermal vessels in sun-exposed skin.

4. Genetic Testing.

Identification of pathogenic variants in the ferrochelatase (FECH) gene, typically in trans with the c.315-48T>C (IVS3-48C) polymorphism, or in the caseinolytic mitochondrial matrix peptidase chaperone subunit X (CLPX) gene.

5. Differential Diagnoses.

i. Sideroblastic anemia.

ii. Iron deficiency anemia.

iii. Hemolytic anemia.

iv. Other porphyrias.

v. Other photodermatoses (e.g., hydroa vacciniforme, polymorphous light eruption, and chronic actinic dermatitis).

4.1.1.1 | Diagnostic Categories. A diagnosis of EPP may be established when either of the following conditions is met:

A. Presence of the clinical symptoms described in (1), together with the laboratory findings in (3-i) showing markedly elevated erythrocyte protoporphyrin levels, after exclusion of the differential diagnoses listed in (5).

B. Presence of at least one of the clinical findings described in (2), together with the identification of a pathogenic variant

4

The Journal of Dermatology, 2026

|||Porphyria type|Heme biosynthetic enzyme|Causative gene/ Chromosomal locus|Mode of inheritance| |---|---|---|---|---|---| |Acute porphyrias|Hepatic|Acute intermittent porphyria (AIP)|Hydroxymethylbilane synthase (HMBS)|HMBS/11q23.3|AD| |Acute porphyrias|Hepatic|Aminolevulinate dehydratase Deficiency porphyria (ADP)|Aminolevulinate dehydratase (ALAD)|ALAD/9q34|AR| |Acute porphyrias|Hepatic|Variegate porphyria (VP)|Protoporphyrinogen oxidase (PPOX)|PPOX/1q22-23|AD| |Acute porphyrias|Hepatic|Hereditary coproporphyria (HCP)|Coproporphyrinogen oxidase (CPOX)|CPOX/3q12|AD| |Cutaneous porphyrias||Porphyria cutanea tarda (PCT)|Uroporphyrinogen decarboxylase (UROD)|UROD/1p34|Acquired (type I)/AD (type II)/unknown (type III)| |Cutaneous porphyrias|Erythropoietic|Hepatoerythropoietic porphyria (HEP)|Uroporphyrinogen decarboxylase (UROD)|UROD/1p34|AR| |Cutaneous porphyrias|Erythropoietic|Congenital erythropoietic porphyria (CEP)|Uroporphyrinogen III synthase (UROS)|UROS/10q25.2-q26.3|AD| |Cutaneous porphyrias|Erythropoietic|Erythropoietic protoporphyria (EPP)|Ferrochelatase (FECH), Caseinolytic mitochondrial matrix peptidase chaperone subunit X (CLPX)|FECH/18q21.3 CLPX/15q22.31|AD/AR| |Cutaneous porphyrias|Erythropoietic|X-linked protoporphyria (XLP)|Aminolevulinate synthase 2 (ALAS2)|ALAS2/Xp11.21|XL|

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked.

as described in (4), after exclusion of the differential diagnoses listed in (5).

4.1.2 | PCT

1. Clinical Symptoms.

Photosensitivity: Following sun exposure, patients develop erythema and swelling with pruritus on sun-exposed areas.

2. Clinical Findings.

i. Cutaneous manifestations: On sun-exposed areas, erythema, vesicles, erosions, scars, hyperpigmentation, and hypertrichosis.

ii. Liver dysfunction.

3. Laboratory Findings.

i. Markedly elevated of urinary uroporphyrins (≥3×ULN) [5], with a marked increase in urinary heptacarboxylporphyrins.

ii. Urinary porphobilinogen(PBG)andδ-aminolevulinic acid (ALA) remain within the normal ranges.

iii. Erythrocyte protoporphyrin and coproporphyrin levels remain within the normal ranges.

iv. Deposition of PAS-positive material around dermal vessels in sun-exposed skin.

4. Genetic Testing.

In familial PCT, heterozygous pathogenic variants in the uroporphyrinogen decarboxylase (UROD) gene may be identified.

5. Differential Diagnoses.

i. Other photosensitivity disorders (e.g., polymorphous light eruption, chronic actinic dermatitis, and drug-induced photosensitivity).

ii. Other porphyrias.

iii. Pseudoporphyria (clinically and histologically similar to PCT, but without porphyrin metabolic abnormalities).

iv. Disorders caused by polyhalogenated aromatic hydrocarbons (e.g., dioxins, poly chlorinated biphenyls [PCBs], and hexachlorobenzene).

6. Notes.

Potential precipitating factors include alcohol consumption, iron supplementation, estrogen therapy, and oral contraceptives.

4.1.2.1 | Diagnostic Categories. A diagnosis of PCT may be established when either of the following conditions is met:

A. Presence of the clinical symptoms described in (1), together with the laboratory findings in (3-i) through (3-iii), after exclusion of the differential diagnoses listed in (5).

B. Presence of at least one of the clinical findings described in (2), together with the identification of a pathogenic variant as described in (4), after exclusion of the differential diagnoses listed in (5).

4.1.3 | CEP

1. Clinical Symptoms.

Photosensitivity: Present from early infancy; even short periods of sun exposure induce erythema, vesicles, erosions, and ulcers on sun-exposed areas.

2. Clinical Findings.

i. Cutaneous manifestations: Erythema, vesicles, ero- sions, pigmentation, depigmentation, the loss of nasal cartilage, auricles, or digits, and hypertrichosis.

ii. Reddish-brown discoloration of teeth ("erythrodontia").

iii. Splenomegaly.

3. Laboratory Findings.

i. Marked increases in urinary uroporphyrins and coproporphyrins.

ii. Marked increases in erythrocyte coproporphyrins.

iii. Hemolytic anemia.

iv. Positive erythrocyte fluorescence.

4. Genetic Testing.

Identification of pathogenic variants in the uroporphyrinogen III synthase (UROS) gene.

5. Differential Diagnoses.

i. Other photosensitivity disorders (e.g., xeroderma pigmentosum and hydroa vacciniforme).

ii. Other porphyrias.

4.1.3.1 | Diagnostic Categories. A diagnosis of CEP may be established when either of the following conditions is met:

A. Presence of the clinical symptoms described in (1), together with laboratory findings (3-i) and (3-iii), after exclusion of the differential diagnoses listed in (5).

B. Presence of at least one of the clinical findings described in (2), together with the identification of a pathogenic variant as described in (4), after exclusion of the differential diagnoses listed in (5).

4.1.4 | XLP

1. Clinical Symptoms.

Photosensitivity: After sun exposure, patients develop painful erythema and edema on sun-exposed areas. In severe cases, vesicles and erosions may develop.

2. Clinical Findings.

i. Cutaneous manifestations: On sun-exposed areas, erythema, edema on sun-exposed sites, pitted facial scars, hyperpigmentation, lichenification, and hypertrichosis.

ii. Liver dysfunction.

3. Laboratory Findings.

i. Markedly elevated erythrocyte protoporphyrin levels.

ii. Urinary porphyrin precursors and porphyrins remain within the normal ranges. iii. Positive erythrocyte fluorescence. iv. Positive photohemolysis test.

v. Deposition of PAS-positive material around dermal vessels in sun-exposed skin.

4. Genetic Testing.

Identification of pathogenic variants in the ALAS2 gene.

5. Differential Diagnoses. i. Sideroblastic anemia. ii. Iron deficiency anemia. iii. Hemolytic anemia. iv. Other porphyrias. v. Other photodermatoses (e.g., hydroa vacciniforme, polymorphous light eruption, and chronic actinic dermatitis).

4.1.4.1 | Diagnostic Categories. A diagnosis of XLP may be established when either of the following conditions is met:

A. Presence of the clinical symptoms described in (1), together with laboratory findings (3-i) and (3-iv), after exclusion of the differential diagnoses listed in (5).

B. Presence of at least one of the clinical findings described in (2), together with the identification of a pathogenic variant as described in (4), after exclusion of the differential diagnoses listed in (5).

4.1.5 | HEP

1. Clinical Symptoms.

Photosensitivity: After sun exposure, patients develop pruritic erythema and edema on sun-exposed areas.

2. Clinical Findings. i. Cutaneous manifestations: Erythema, vesicles, ero-sions, scarring, hyperpigmentation, and hypertricho-sis on sun-exposed sites. ii. Liver dysfunction.

3. Laboratory Findings. i. Marked increases in urinary uroporphyrins and heptacarboxylporphyrins. ii. Urinary PBG and ALA remain within the normal ranges. iii. Elevated erythrocyte protoporphyrin levels. iv. Deposition of PAS-positive material around dermal vessels in sun-exposed skin. 4. Genetic Testing.

Identification of biallelic pathogenic variants in the UROD gene.

5. Differential Diagnoses. i. Other photodermatoses (e.g., polymorphic light eruption, chronic actinic dermatitis, and drug-induced photosensitivity).

ii. Other porphyrias. iii. Pseudoporphyria (porphyria-like clinical and histological findings without porphyrin metabolism abnormalities). iv. Disorders caused by polyhalogenated aromatic hydrocarbons (e.g., dioxins, PCBs, and hexachlorobenzene).

6. Remarks.

Potential triggering factors include alcohol consumption, iron therapy, estrogen administration, and oral contraceptives.

4.1.5.1 | Diagnostic Categories. A diagnosis of HEP may be established when either of the following conditions is met:

A. Presence of the clinical symptoms described in (1), together with the laboratory findings in (3-i) to (3-iii), after exclusion of the differential diagnoses listed in (5).

B. Presence of at least one of the clinical findings described in (2), together with the identification of a pathogenic variant as described in (4), after exclusion of the differential diagnoses listed in (5).

4.2 | Diagnostic Criteria for Acute Porphyrias

4.2.1 | AIP

1. Clinical Features. i. Onset typically occurs after puberty, often with acute episodes.

ii. Gastrointestinal symptoms: abdominal pain of varying intensity, vomiting, and constipation.

iii. Neuropsychiatric symptoms: limb weakness, seizures, and psychiatric disorders.

iv. Autonomic symptoms: hypertension, tachycardia, and fever.

v. Cutaneous manifestations (photosensitivity) are absent.

2. Laboratory Findings (during attacks) [5, 6]. i. Marked increase in urinary ALA, ≥ 3 × ULN. ii. Marked increase in urinary PBG, ≥ 5 × ULN. During remission, urinary ALA and PBG levels may remain elevated, at approximately ≥ 2 × ULN.

3. Genetic Testing.

Identification of pathogenic variants in the hydroxymethylbilane synthase (HMBS) gene.

4. Differential Diagnoses.

i. Acute abdomen due to organic lesions.

ii. Ileus.

iii. Appendicitis.

iv. Dissociative disorders.

v. Lead poisoning.

vi. Other porphyrias.

5. Remarks

i. A positive family history may be present.

ii. A personal history of similar symptoms may be noted.

TABLE 3 | Triggers, precipitating drugs, and attack-provoking agents [7].

(1) Non-drug triggers

Infection; overwork; surgery; trauma; pregnancy; menstruation; fasting/starvation; excessive psychological stress; thyroid hormones.

(2) Precipitating drugs

Barbiturates; sulfonamides; meprobamate; phenytoin; chlordiazepoxide; alcohol; chloroquine; sulfonal; trional; ergot alkaloids; sulfonylureas; methyldopa; pyrazolones; glutethimide; imipramine; estrogens; gestagens (progestogens); 5β-hydroxysteroids; chloramphenicol; methoximide; pentazocine.

(3) Attack-provoking agents

Allylisopropylacetylurea; allylisopropylacetamide; 3,5-diethoxycarbonyl-1,4-dihydrocollidine; carbamazepine; griseofulvin; hexachlorobenzene; mphenytoin; fensuximide.

Note: Adapted from: Sasaki et al. [7].

iii. Precipitating factors include certain drugs (e.g., barbiturates, sulfonamides, anticonvulsants, oral contraceptives, and estrogen preparations), hormonal changes (e.g., premenstrual, pregnancy, and postpartum), smoking, alcohol consumption, infections, caloric restriction, and various stressors (Table 3 [7], CQ8).

4.2.1.1 | Diagnostic Categories. A diagnosis of AIP may be established when either of the following conditions is met:

A. Presence of at least one of the clinical features described in (1), together with both laboratory findings in (2-i) and (2-ii), after exclusion of the differential diagnoses listed in (4).

B. Presence of at least one of the clinical features described in (1), together with the identification of a pathogenic variant as described in (3), after exclusion of the differential diagnoses listed in (4).

4.2.2 | HCP

1. Clinical Features. i. Onset typically occurs after puberty, often with acute episodes. ii. Gastrointestinal symptoms: abdominal pain of varying severity, vomiting, and constipation. iii. Neuropsychiatric symptoms: limb weakness, seizures, and psychiatric disorders. iv. Autonomic symptoms: hypertension, tachycardia, and fever. v. Cutaneous manifestations (photosensitivity) may occur.

2. Laboratory Findings (during attacks). i. Marked increases in urinary ALA, ≥1.5 × ULN and urinary PBG, ≥2 × ULN. ii. Marked increases in urinary uroporphyrins (≥2 × ULN) and coproporphyrins (≥3 × ULN). iii. Normal erythrocyte protoporphyrin levels. During remission, urinary ALA and PBG levels usually return to normal.

3. Genetic Testing.

Identification of pathogenic variants in the coproporphyrinogen oxidase (CPOX) gene.

4. Differential Diagnoses. i. Acute abdomen due to organic lesions (e.g., biliary colic and urolithiasis). ii. Ileus. iii. Appendicitis. iv. Dissociative disorders. v. Lead poisoning. vi. Other porphyrias.

5. Remarks. i. A positive family history may be present. ii. A personal history of similar symptoms may be noted.

iii. Precipitating factors include certain drugs, hormonal imbalance (e.g., premenstrual, pregnancy, and postpartum), smoking, alcohol consumption, infections, caloric restriction, and various stressors.

4.2.2.1 | Diagnostic Categories. A diagnosis of HCP may be established when either of the following conditions is met:

A. Presence of at least one of the clinical features described in (1), together with all of the laboratory findings in (2-i) to (2-iii), after exclusion of the differential diagnoses listed in (4).

4.2.3 | VP

1. Clinical Features. i. Onset typically occurs after puberty, often with acute episodes. ii. Gastrointestinal symptoms: abdominal pain of varying severity, vomiting, and constipation. iii. Neuropsychiatric symptoms: limb weakness, seizures, and psychiatric disorders.

iv. Autonomic symptoms: hypertension, tachycardia, and fever.

v. Cutaneous manifestations (photosensitivity) are present.

2. Laboratory Findings (during attacks).

i. Marked increases in urinary ALA, ≥1.5 × ULN, and PBG, ≥1.5 × ULN.

ii. Marked increases in urinary uroporphyrins (≥2 × ULN) and coproporphyrins (≥4 × ULN).

iii. Normal erythrocyte protoporphyrin levels. During remission, urinary ALA and PBG levels usually normalize.

3. Genetic Testing.

Identification of pathogenic variants in the protoporphyrinogen oxidase (PPOX) gene.

4. Differential Diagnoses.

i. Acute abdomen due to organic lesions (e.g., biliary colic and urolithiasis).

ii. Ileus.

iii. Appendicitis.

iv. Dissociative disorders.

v. Lead poisoning.

vi. Other porphyrias.

5. Remarks.

i. A positive family history may be present.

ii. A personal history of similar symptoms may be noted.

iii. Precipitating factors include certain drugs, hormonal imbalance (e.g., premenstrual, pregnancy, and post-partum), smoking, alcohol consumption, infections, caloric restriction, and various stressors.

iv. Increases in fecal coproporphyrins and protoporphyrins may also be observed.

4.2.3.1 | Diagnostic Categories. A diagnosis of VP may be established when either of the following conditions is met:

A. Presence of at least one of the clinical features described in (1), together with all of the laboratory findings in (2-i) to (2-iii), after exclusion of the differential diagnoses listed in (4).

B. Presence of at least one of the clinical features described in (1), together with the identification of a pathogenic variant as described in (3), after exclusion of the differential diagnoses listed in (4).

4.2.4 | ADP

1. Clinical Features.

i. Onset commonly occurs in childhood, often with acute episodes.

ii. Gastrointestinal symptoms: abdominal pain of varying severity, vomiting, and constipation.

iii. Neuropsychiatric symptoms: limb weakness, seizures, and psychiatric disorders.

iv. Autonomic symptoms: hypertension, tachycardia, and fever.

v. Cutaneous manifestations (photosensitivity) are absent.

2. Laboratory Findings (during attacks).

i. Marked increases in urinary ALA, ≥8 × ULN.

ii. Marked increases in urinary coproporphyrins, ≥8×ULN.

iii. Urinary PBG ranges from normal to up to 5× ULN.

iv. Marked increase in erythrocyte zinc-protoporphyrin.

3. Genetic Testing.

Identification of pathogenic variants in the aminolevulinate de-hydratase (ALAD) gene.

4. Differential Diagnoses.

i. Acute abdomen due to organic lesions.

ii. Ileus.

iii. Appendicitis.

iv. Dissociative disorders.

v. Lead poisoning.

vi. Tyrosinemia.

vii. Other porphyrias.

5. Remarks.

i. A positive family history may be present.

ii. A personal history of similar symptoms may be noted.

iii. Precipitating factors include certain drugs, hormonal imbalance (e.g., menstruation, pregnancy, and post-partum), smoking, alcohol consumption, infections, caloric restriction, and stress.

iv. Elevated PBG is often absent.

4.2.4.1 | Diagnostic Categories. A diagnosis of ADP may be established when either of the following conditions is met:

A. Presence of at least one of the clinical features described in (1), together with laboratory findings (2-i) and (2-ii), after exclusion of the differential diagnoses listed in (4).

B. Presence of at least one of the clinical features described in (1), together with the identification of a pathogenic variant as described in (3), after exclusion of the differential diagnoses listed in (4).

4.3 | Severity Classification

A case is classified as severe if any one of the following clinical criteria is met:

1. Photodermatitis with blisters or erosions exceeding the size of the patient's palm.

2. Complete loss of function of the fingers or an equivalent disability

3. Abdominal colic attacks requiring hospitalization at least twice within the past year.

4. Diarrhea with dehydration requiring hospitalization at least twice within the past year.

5. Constipation with symptoms of intestinal obstruction requiring hospitalization at least twice within the past year.

6. Hepatic dysfunction of Child-Pugh Class B or higher. 7. Hemolytic anemia with hemoglobin levels below 10.0 g/dL. 8. In acute porphyrias, the presence of paresis, impaired consciousness, bulbar symptoms, or hyponatremia.

5 | Epidemiology

In Japan, the first porphyria case was reported in 1920, and 926 cases were documented over the following 91 years up to 2010 [8]. The most frequent subtypes were PCT (35.4%), EPP (21.9%), and AIP (21.4%). HEP and ADP were extremely rare (<1%). A nationwide survey in 2009 estimated 208 patients annually, with EPP being the most common (109 cases) [9]. A subsequent survey in 2018–2019 identified 197 cutaneous porphyria patients, including 179 with EPP [10]. Regionally, porphyrias are more prevalent in western Japan. Most Japanese PCT cases are acquired; familial PCT, which accounts for 20%–30% of cases internationally, has been reported in only 4 Japanese families, with a pathogenic UROD variant confirmed in one [11]. XLP has been reported in a single Japanese family with three affected members [12].

Porphyrias are distributed worldwide but show regional variations. AIP is more common in Scandinavia (1.5/100000 people), while VP is frequent in South Africa (3/1000 people) [13]. However, true prevalence remains uncertain due to their rarity, asymptomatic intervals in acute porphyrias, the incomplete penetrance of genetic variants, and the transient or mild nature of photosensitivity in some EPP cases [14].

6 | Etiology and Pathophysiology

Hereditary porphyrias are rare genetic disorders caused by pathogenic variants in genes encoding enzymes of the heme biosynthetic pathway, leading to the excess production and accumulation of porphyrins or their precursors, which, in turn, cause diverse clinical manifestations [2, 15]. Nine enzymes are involved in heme synthesis. Pathogenic variants that reduce or increase enzymatic activity underlie the pathogenesis of hereditary porphyrias. Heme synthesis begins in mitochondria with the condensation of glycine and succinyl-CoA catalyzed by ALAS, producing ALA. ALA then translocates into the cytoplasm, undergoes a series of enzymatic reactions to generate co-proporphyrinogen III, and re-enters mitochondria for the final steps of heme synthesis (Figure 1) [15]. ALAS has two isoforms: ALAS1, expressed ubiquitously; and ALAS2, expressed specifically in erythroid cells [16]. Pathogenic variants in ALAS2 cause XLP. The clinical features of porphyrias result from the accumulation of porphyrins and toxic intermediates upstream of the enzymatic block [17].

6.1 | Cutaneous Porphyrias

The pathogenesis of cutaneous manifestations, mainly photo-sensitivity, involves porphyrins accumulated in erythrocytes and fibroblasts. Upon cutaneous exposure to sunlight, these porphyrins absorb photons and generate reactive oxygen species

(ROS) and lipid peroxides. These mediators damage cell membranes in erythrocytes and fibroblasts, stimulate inflammatory cytokines, such as interleukin (IL)-1 and IL-6, and activate colagenases, collectively leading to erythema, blistering, and other skin lesions [18, 19].

6.1.1 | EPP

EPP is mainly caused by pathogenic variants in the FECH gene and, less commonly, in the CLPX gene. Most cases result from FECH deficiency with autosomal dominant inheritance, but penetrance is low, estimated at around 10% in Europe. This low penetrance is explained by the requirement for coinheritance of the intronic polymorphism IVS3-48C in trans. This polymorphism reduces FECH messenger ribonucleic acid (mRNA) expression, and when present together with a pathogenic FECH variant, residual enzyme activity falls to about 30%, leading to disease manifestation [20]. The allele frequency of IVS3-48C is approximately 45% in Japanese (about 6 times higher than in Europeans), which likely accounts for the higher penetrance of EPP in Japan [21]. In some Japanese patients carrying IVS3-48C without FECH variants, mild photosensitivity and a modest erythrocyte protoporphyrin elevation have been reported, termed incomplete EPP [22]. Autosomal recessive forms with biallelic FECH variants have also been described [23].

Approximately 80% of protoporphyrin in EPP is produced in erythroid precursors of the bone marrow and approximately 20% in the liver [24]. Mature erythrocytes contain excess free protoporphyrin, some of which circulates bound to plasma albumin. Most protoporphyrin is excreted unchanged into bile, although a portion undergoes enterohepatic circulation before elimination in feces. FECH normally inserts iron into protoporphyrin to form heme, but can also incorporate other metals, such as zinc. In EPP, decreased FECH activity impairs both heme and zinc–protoporphyrin synthesis, resulting in a predominance (approximately 85%–100%) of metal-free protoporphyrin [3, 25, 26]. When erythrocytes containing large amounts of protoporphyrin are exposed to light within dermal capillaries, protoporphyrin becomes photoexcited and generates ROS. These ROS damage erythrocytes, vascular endothelial cells, and surrounding tissues, leading to erythema, purpura, and blister formation [27–31]. Complement activation and mast cell degranulation may also contribute.

When hepatic clearance capacity is exceeded, lipophilic protoporphyrin precipitates in bile canaliculi or crystallizes within hepatocytes, inducing cholestatic liver injury. Persistent accumulation may progress to hepatic fibrosis and, in rare cases, liver failure. Only a few percent of patients with EPP develop liver failure, and the specific factors leading to irreversible hepatic injury remain unclear [24]. Patients with autosomal recessive EPP have lower FECH activity than those with autosomal dominant EPP and exhibit a higher frequency of hepatic complications [32]. Furthermore, the risk of liver injury markedly increases when erythrocyte protoporphyrin levels exceed 1500 µg/dL red blood cells (RBC) [33]. Patients with hepatic dysfunction show significantly higher erythrocyte protoporphyrin levels than unaffected individuals, and those with severe disease exhibit higher levels than patients with mild-to-moderate disease

![graph TD\n A1[Succinyl CoA and glycine] --> A2[δ-aminolevulinic acid(ALA)]\n A2 --> A3[Porphobilinogen(PBG)]\n A2 -->|Enzyme name: δ-aminolevulinic acid synthase[ALAS]| A7[Related porphyria: XLP]\n A3 --> A4[Hydroxymethylbilane(HMB)]\n A3 -->|Enzyme name: aminolevulinate dehydratase[ALAD]| A8[Related porphyria: ADP]\n A4 --> A5[Uroporphyrinogen III(Uro’gen III)]\n A4 -->|Enzyme name: Hydroxymethylbilane synthase[HMBS]| A9[Related porphyria: AIP]\n A5 --> A6[Coproporphyrinogen III(Copro’gen III)]\n A5 -->|Enzyme name: Uroporphyrinogen III Synthase[UROS]| A10[Related porphyria: CEP]\n A6 --> A7\n A6 -->|Enzyme name: Uroporphyrinogen Decarboxylase[UROD]| A11[Related porphyria: PCT, HEP]\n A6 --> A8\n A6 --> A9\n A6 --> A10\n A6 --> A11\n A6 --> A12[Coproporphyrinogen Oxidase(CPOX)]\n A6 -->|Enzyme name: Coproporphyrinogen Oxidase[CPOX]| A13[Related porphyria: HCP]\n A6 --> A14[Protoporphyrinogen IX(Proto’gen IX)]\n A6 -->|Enzyme name: Protoporphyrinogen oxidase[PPOX]| A15[Related porphyria: VP]\n A6 --> A16[Protoporphyrin IX(PplX)]\n A6 -->|Enzyme name: Ferrochelatase[FECH]| A17[Related porphyria: EPP]\n A6 --> A18[HEME]\n A14 --> A16\n A14 -->|Enzyme name: Protoporphyrinogen oxidase[PPOX]| A15\n A16 --> A18\n A16 -->|Enzyme name: Ferrochelatase[FECH]| A17\n A18 --> A19[Biliverdin + carbon monoxide + iron]\n A18 --> A21[Cytochrome P-450(liver)]\n A18 --> A22[Hemoglobin(bone marrow)]\n A19 --> A20[Bilirubin]\n A19 -->|Enzyme name: Ferrochelatase[FECH]| A17\n A19 -->|Enzyme name: Biliverdin reductase[BVR]| A20\n](1/parseimages/figurea34a63c4c8e747afbcb76caa52a2bb4c_0_0.png) [34]. Collectively, these findings indicate that elevated erythrocyte protoporphyrin levels are strongly associated with an increased risk of hepatic complications (CQ11).

CLPX, more recently implicated in EPP, regulates the synthesis and degradation of ALAS2 in erythroid cells. Loss of CLPX function leads to ALAS2 up-regulation and protoporphyrin overproduction [35]. No Japanese cases have been reported to date.

6.1.2 | PCT

PCT results from the genetic or acquired deficiency of UROD, causing the hepatic accumulation of uroporphyrinogen, which oxidizes to uroporphyrins and deposits in the skin, leading to photosensitivity. PCT is classified into sporadic PCT (type I),

caused by the acquired inhibition of UROD, and familial PCT (type II), an autosomal dominant disorder due to UROD variants [36]. Type III PCT is rarely reported, with familial clustering but no detectable UROD variant [37].

Sporadic PCT is frequently associated with environmental triggers, including alcohol consumption, smoking, estrogen therapy, iron overload, HCV infection, human immunodeficiency virus infection, aromatic hydrocarbons, hexachlorobenzene, dioxins, and hemodialysis [37–40]. Iron overload plays a central role by promoting oxidative stress, increasing porphyrin production, and elevating intracellular ALA levels [41–43]. In Western populations, pathogenic variants in the human homeostatic iron regulator gene have been implicated, but no such cases have been reported in Japan [41]. Even in familial PCT, additional acquired triggers are generally required for clinical manifestation.

6.1.3 | CEP

CEP is an autosomal recessive disorder caused by a deficiency of UROS, resulting in the systemic accumulation of type I porphyrin isomers (uroporphyrin I and coproporphyrin I). These isomers accumulate in tissues and are excreted in urine and feces, comprising more than 85% of the total porphyrin fraction [44]. Clinically, CEP is characterized by severe photosensitivity, hemolytic anemia, and splenomegaly. Most cases are attributable to pathogenic variants in UROS, but variants in GATA-binding transcription factor 1 (GATA1) and ALAS2 have also been reported [45–47]. Residual UROS activity inversely correlates with disease severity [48].

6.1.4 | XLP

XLP is an extremely rare disorder caused by gain-of-function variants in ALAS2, which increase enzyme activity and enhance protoporphyrin production [49, 50]. Unlike EPP, FECH activity is preserved, leading to markedly elevated total protoporphyrin levels with a higher proportion of zinc-protoporphyrin and a lower fraction of free protoporphyrin in EPP [25]. Female carriers in particular may present with variable phenotypes due to X-chromosome inactivation [49, 50].

6.1.5 | HEP

HEP is an autosomal recessive disorder caused by biallelic UROD variants [51]. Patients present with severe photosensitivity and the markedly increased urinary excretion of uroporphyrin. Erythrocytes show markedly elevated protoporphyrin levels, composed predominantly of zinc–protoporphyrin, which distinguishes HEP from familial PCT [51].

6.2 | Acute Porphyrias

In acute porphyrias, clinical manifestations result from the excess accumulation of porphyrin precursors, especially ALA, which has neurotoxicity [17]. The overproduction and accumulation of ALA cause severe abdominal pain, nausea, vomiting, constipation, muscle weakness, peripheral neuropathy, tachycardia, hypertension, headache, and altered consciousness. Disease onset requires both genetic enzyme deficiency and precipitating factors such as medications, supplements, menstruation, pregnancy, hormonal contraceptives, infections, fasting, stress, or alcohol consumption (Table 3 [7]). The hallmark of acute porphyrias is recurrent acute attacks triggered by these external factors in genetically predisposed individuals.

Acute porphyrias comprise AIP, VP, HCP, and ADP. AIP, VP, and HCP show autosomal dominant inheritance, while ADP shows autosomal recessive inheritance and is extremely rare, with fewer than 10 reported cases worldwide and none in Japan. All are characterized by marked increases in ALA during attacks, although the specific enzyme defect, accumulated metabolites, and clinical features vary (Table 4 [37, 52, 53], Table 5 [54]).

The degree of precursor accumulation depends on heme demand. Under normal conditions, ALAS1 is the rate-limiting enzyme, keeping precursor accumulation minimal. However, when heme demand increases, ALAS1 expression is up-regulated, unmasking downstream enzyme deficiencies and promoting excess ALA accumulation. In HCP and VP, accumulated coproporphyrinogen III and protoporphyrinogen IX can further inhibit HMBS activity, amplifying ALA accumulation [55]. In other words, acute attacks occur when there is an increased demand for heme synthesis due to acquired factors. The mechanisms inducing acute porphyria attacks include im-posing an enzymatic load as selective inducers of the porphyrin synthesis pathway or directly impairing porphyrin biosynthetic enzymes.

The mechanisms underlying neurological dysfunction are not fully understood; however, two major hypotheses have been proposed: the ALA neurotoxicity hypothesis and the heme deficiency hypothesis. According to the ALA neurotoxicity hypothesis, ALA crosses the blood-brain barrier, is toxic to cultured glial and neuronal cells, and generates ROS in the presence of iron that damage neurons [56–62]. Due to structural similarities with γ-aminobutyric acid (GABA), ALA may also act as a GABA agonist, disrupting neurotransmission, impairing gut motility, and contributing to neurological and gastrointestinal symptoms [63–66]. In vivo studies also suggest that ALA can inhibit melatonin release from the pineal gland via GABA-mediated pathways [66]. The heme deficiency hypothesis proposes that reduced heme availability impairs mitochondrial cytochromes and other hemoproteins necessary for oxidative phosphorylation, leading to decreased adenosine triphosphate production, Na$^{+}$/K$^{+}$ pump dysfunction, impaired axonal transport, and neuronal energy failure [67]. The rapid clinical improvement in acute attacks with heme therapy strongly supports the heme deficiency hypothesis.

7 | Clinical Manifestations

Porphyrias present with three major categories of symptoms: cutaneous, gastrointestinal, and neuropsychiatric (Table 4) [37, 52, 53]. Cutaneous symptoms are almost universally attributable to photosensitivity and are shared across several subtypes, whereas gastrointestinal and neuropsychiatric symptoms occur only in acute porphyrias. Each subtype also exhibits distinct clinical features.

7.1 | Cutaneous Porphyrias

Cutaneous manifestations can be broadly divided into acute and chronic phases. Acute-phase lesions resemble photodermatitis, with pruritus, erythema, edema, vesicles, erosions, crusts, pura, and onycholysis appearing sequentially after sun exposure. Chronic-phase lesions include pruritus, scarring, hyperpigmentation, hypopigmentation, skin fragility, waxy thickening, lichenification, milia, hypertrichosis, scarring alopecia, peroral pseudo-fissures, sclerodermoid changes, ectropion, digital mutilation, nasal or auricular defects, and calcification. Not all lesions are seen in every case, as manifestations depend on antecedent acute events. In general, cutaneous symptoms are the

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The Journal of Dermatology, 2026

|Porphyria type|Age at onset|Clinical features|Neurovisceral symptoms|Cutaneous manifestations|Anemia|Hepatic involvement| |---|---|---|---|---|---|---| |Acute intermittent porphyria (AIP)|3rd to 4th decade of life, usually not before the onset of puberty|Acute neurovisceral attacks, no skin changes; potential complication: hepatocellular carcinoma (HCC).|++|-|-|-/+| |Aminolevulinate dehydratase deficiency porphyria (ADP)|Variable; manifestation reported in both children and adults|Acute neurovisceral attacks, no skin changes.|++|-|-/+|-| |Variegate porphyria (VP)|3rd to 4th decade of life, usually not before the onset of puberty|Mild-to-moderate photosensitivity; skin changes confined to sun-exposed areas: increased skin fragility, vesicles/bullae, erosions, crusts, milia, scars, hyperpigmentation, hypertrichosis; acute neurovisceral attacks; potential complication: HCC.|++|-/+|-|-/+| |Hereditary coproporphyria (HCP)|Usually not before puberty|Cutaneous manifestations are much rarer than in VP; mild-to-moderate photosensitivity; skin changes confined to sun-exposed areas: increased skin fragility, vesicles/bullae, erosions, crusts, milia, scars, hyperpigmentation; acute neurovisceral attacks; potential complication: HCC.|++|-/+|-|-/+| |Porphyria cutanea tarda (PCT)|5th-6th decades of life, usually not before puberty|Mild-to-moderate photosensitivity; increased skin fragility, skin changes confined to sun-exposed areas: vesicles/bullers, erosions, crusts, milia, scars, hyperpigmentation, sclerodermiform papules and plaques, hypertrichosis; potential complication: hepatic cirrhosis, HCC.|-|+|-|+| |Hepatoerythropoietic porphyria (HEP)|Early childhood|Moderate-to-severe photosensitivity; skin changes confined to sun-exposed areas: increased skin fragility, vesicles/bullae, erosions, crusts, milia, scars, hyperpigmentation, hypertrichosis, mutilations (including digital autoamputation).|-|++|-/+|+|

(Continues)

||Age at onset|Clinical features|Neurovisceral symptoms|Cutaneous manifestations|Aennia involvement| |---|---|---|---|---|---| |Congenital erythropoetic porphyria (EPP)|Early childhood/ninfancy|Moderate-to-very severe photosensitivity; skin changes confine areas: increased skin fragility, vesicles; bullae, erosions, crucists, mila, scars, hypertrichosis.|–|++|–| |Erythropoetic preporphyria (EPP)|Early childhood|Moderate-to-severe photosensitivity. Subjective symptoms: burning, sing, and pain of the skin immediately after light exposure. Objective findings on sun-exposed areas: postinflammatory by prepgimentation; diffuse erythema and eddeminary hypertrichation; postinflammatory by prepgimentation; less commonly petecile and purpura; comations: chohlathis; liver failure.|–|++|–| |Erythropoetic preporphyria (EPP)|Early childhood|–|–|–|–| |X-linked protoporphyria (XLP)|Early childhood|Moderate-to-severe photosensitivity. Subjective symptoms: burning, sing, and pain of the skin immediately after light exposure. Objective findings on self-inmediary and purpura; compations: chohlathis; liver failure.|–|–|–| |X-linked protoporphyria (XLP)|Early childhood|Moderate-to-severe photosensitivity. Subjective symptoms: burning, sing, and pain of the skin immediately after light exposure. Objective findings on self-inmediary and purpura; compations: chohlathis; liver failure.|–|–|–|

TABLE 5 | Initial subjective symptoms at onset of acute porphyrias [54].

||AIP (N=198)|VP (N=56)|HCP (N=41)|Unclassified (N=58)|Total (N=353)| |---|---|---|---|---|---| |Gastrointestinal symptoms|||||| |Abdominal pain|165|37|31|45|278| |Vomiting|76|29|26|26|157| |Constipation|38|14|10|19|81| |Diarrhea|8|1|4|0|13| |Neurologic symptoms|Neurologic symptoms|Neurologic symptoms|Neurologic symptoms|Neurologic symptoms|Neurologic symptoms| |Weakness and motor paralysis|25|18|13|6|62| |Sensory disturbance in the extremities|23|11|10|1|45| |Speech disturbance|1|4|1|1|7| |Dysphagia|1|3|1|0|5| |Seizures|5|1|4|5|15| |Impaired consciousness|1|0|1|0|2| |Cutaneous symptoms|Cutaneous symptoms|Cutaneous symptoms|Cutaneous symptoms|Cutaneous symptoms|Cutaneous symptoms| |Solar erythema|0|14|3|1|118| |Hyperpigmentation|0|11|4|0|15| |Dark-brown urine|35|16|12|11|74|

Note: Reproduced with permission from: Kondo [54].

most severe in ECP, followed by PCT, and are relatively mild in EPP. Blister formation is common in ECP and PCT but uncommon in EPP, which typically presents with painful photosensitivity. The severity of phototoxicity depends on the deposited porphyrin, with uroporphyrin deposition being the most severe, followed by coproporphyrin and then protoporphyrin [68].

7.1.1 | EPP

EPP typically manifests in early childhood with increasing sun exposure; in Japan, the median age of onset is 6 (range, 0–25) years old [69]. Mild cases may be mistaken for sunburn. Short sun exposure induces burning, tingling, or pain, sometimes without visible erythema, and symptoms typically appear 30–60 min after exposure [70]. Acute lesions consist of diffuse erythema and edema on sun-exposed areas, occasionally with purpura or petechiae [71–73]. Vesicles are rare [52, 74]. Chronic findings include atrophic or linear scars, waxy thickening, and lichenification, particularly on the cheeks, where a shiny, oily appearance is characteristic. In well-protected patients, only a few small depressed scars scars on the cheeks may be evident. Edematous erythema and erosions may develop on the lower lip, and prolonged exposure may cause photo-onycholysis. Milia, scleroderma-like changes, and red-stained teeth are absent. Higher erythrocyte protoporphyrin levels are associated with more severe skin symptoms.

Liver dysfunction is the most clinically relevant complication, with elevated serum transaminases in about 30% and progression to

liver failure in a few patients. Gallstones occur in about 20% [75], and mild anemia in about 40% [76]. Neurological symptoms are rare and usually occur in patients with hepatic involvement [75].

7.1.2 | PCT

Sporadic PCT typically presents in middle age, whereas familial PCT often manifests before the age of 20 [43]. Cutaneous symptoms and liver dysfunction are characteristic, while neuropsychiatric symptoms are absent. Acute-phase lesions include erythema, vesicles, erosions, and crusts; chronic findings include pruritrus, scarring, skin fragility, milia, and hyperpigmentation. Some patients also develop sclerodermoid changes or hypertrichosis [77, 78]. Facial calcification and diffuse actinic elastosis have been reported. Severity varies widely from minimal to severe. Excess uroporphyrins can cause the urine to appear brown or reddish-brown [15]. Systemic manifestations reflect underlying liver disease, and patients with PCT have an increased risk of hepatocellular carcinoma (HCC) [43].

7.1.3 | CEP

CEP is characterized by lifelong severe photosensitivity and extreme skin fragility. Most patients develop intense photosensitivity soon after birth [53]. Red urine and reddish-brown discoloration of the teeth (erythrodontia) are characteristic early signs [53, 79, 80]. Photosensitivity causes erythema, vesicles, erosions, and crusts, followed by marked fibrosis and scarring.

Recurrent inflammation leads to nail deformities; mutilation of the fingers, ears, nose, or eyelids; scarring alopecia; and areas of hyper- and hypopigmentation [81]. Hypertrichosis is common, and murine models also show adnexal proliferation [82], although the mechanism is unclear.

Hematologic complications include hemolytic anemia and sple-nomegaly; secondary hypersplenism may cause pancytopenia with worsening anemia, bleeding tendency, and infection risk. Ocular involvement (corneal, conjunctival, or sceral lesions) is uncommon but can cause blindness [83]. Porphyrin deposition in hard tissues leads to erythrodontia, osteoporosis, osteodys-trophy, and bone pain [84]. Erythrodontia mainly affects decid-uous teeth and fluoresces red under ultraviolet (UV) light [80]. Severity ranges from hydrops fetalis to mild photosensitivity in adulthood [85, 86]. Later onset (> 10 years old) is associated with milder symptoms and a better prognosis [87].

7.1.4 | XLP

The clinical symptoms of XLP typically present similarly to EPP, with an onset in childhood. Sun exposure causes painful erythema and burning sensations. Chronic lesions include lichenification and atrophic scars on sun-exposed areas, such as the face and hands [72]. Blisters and severe chronic changes are rare. Distinction from EPP requires genetic testing [12]. Protoporphyrin levels are generally higher than in EPP, with more severe cutaneous manifestations and a higher frequency of hepatic involvement; cirrhosis and liver failure can develop [49, 88].

7.1.5 | HEP

HEP presents in childhood with severe skin involvement resembling a combination of PCT and CEP [89]. Patients show marked photosensitivity with acute erythema, vesicles, erosions, pruritus, and pain; some improve after childhood [90]. Other features include skin fragility, hypertrichosis, pigmentation, and sclerodermoid changes [91]. Recurrent blistering and erosions cause severe scarring, digital mutilation, phalangeal shortening, facial or auricular contractures, bone resorption, and joint deformities [90]. Red urine and erythrodontia are sometimes observed. More than 50% of patients have anemia, although transfusion is rarely required [90]. Splenomegaly may occur, and hemolytic anemia is possible. Neurological complications, such as developmental delay and seizures have been reported [92, 93]. Since the introduction of genetic testing, milder cases have been recognized [90, 94], often with a relatively late onset and minimal photosensitivity.

7.2 | Acute Porphyrias

7.2.1 | Acute Attacks

All four acute porphyrias are characterized by acute attacks showing severe neurological dysfunction and the classic triad of abdominal, neurological, and psychiatric symptoms [15]. Except for ADP, disease penetrance is low and most carriers remain asymptomatic [95]. Symptomatic cases occur more often in women than in men, typically beginning after menarche and

markedly decrease after menopause. The most frequent manifestations and their prevalence are summarized in Table 5 [54].

Diffuse, severe abdominal pain occurs in more than 80% of attacks [96]. Guarding and rebound are typically absent. Nausea, vomiting, and constipation are common. Imaging is usually unremarkable except for possible signs of ileus. These gastrointestinal symptoms reflect autonomic dysfunction. Pain is often severe, leading to a misdiagnosis of an acute abdomen and unnecessary surgical intervention. Symptoms typically worsen over several days and resolve gradually within 1 to 2 weeks.

Neurological symptoms occur in up to 70% [96], affecting peripheral, central, and autonomic systems [97]. Peripheral neuropathy usually begins with proximal weakness and progresses distally. About half develop sensory symptoms, such as pares-thesia or numbness. Some cases progress within days to flac-cid quadriparesis with respiratory failure requiring mechanical ventilation. Central involvement occurs in 50%–75%; symptoms range from headache, anxiety, sleep disturbance, and chronic fa-tigue to depression, psychosis, and coma [98]. Seizures occur in up to 20%. Other findings include visual disturbances, Babinski signs, nystagmus, cerebellar ataxia, and posterior reversible en-cephalopathy syndrome [99]. Autonomic dysfunction underlies both gastrointestinal symptoms and cardiovascular signs, such as tachycardia and hypertension.

Hyponatremia occurs in about 25%–60% of attacks, often due to a syndrome of inappropriate antidiuretic hormone secretion, reflecting hypothalamic with autonomic involvement.

7.2.2 | Chronic Symptoms

Most patients experience only one or a few attacks in their lifetime, but a subset of patients develop recurrent episodes. In the EXPLORE natural history study, 65% of patients with recurrent attacks reported chronic symptoms (pain, fatigue, anxiety, and nausea), and 46% had daily symptoms [100]. Similar patterns have been reported in Japan [101]. These patients have high rates of depression, anxiety, and insomnia, with a markedly disturbed quality of life (QOL) [100, 102]. Persistently elevated urinary ALA and PBG levels are common [103]. Whether chronic symptoms arise from repeated severe attacks or from irreversible neuronal injury due to sustained ALA elevation remains unclear.

Long-term risks include chronic liver disease, HCC, and chronic kidney disease (CKD) [101, 104, 105]. Although these risks are less well defined in asymptomatic carriers with elevated por-phyrin precursors than in symptomatic patients, regular follow-ups are recommended. Notably, cutaneous photosensitivity resulting from porphyrin accumulation occurs in VP and HCP, but not in AIP or ADP [106].

8 | Diagnostic Tests

8.1 | Cutaneous Porphyrias

An accurate diagnosis of cutaneous porphyrias requires clinical suspicion based on photosensitivity and age of onset. Since many

disorders present with photosensitivity, prompt screening tests are essential. When abnormalities are identified, further biochemical and genetic testing is required to establish the subtype.

8.1.1 | Screening Tests

Differential diagnoses of cutaneous porphyrias include a broad range of photodermatoses and disorders exacerbated by light exposure (Table 6). Phototesting is useful as a first step in the differential diagnosis. In porphyrias, erythema may be induced by UVA and/or visible light, although findings may occasionally be absent. Genovese et al. reported that among 20 cases of EPP and 1 case of XLP, photosensitivity was observed in 9 (42.9%) with UVA and 8 (38.1%) with visible light exposure [107]. In EPP and XLP, erythrocyte fluorescence can be observed in peripheral blood smears under a fluorescence microscope. In addition, the photohemolysis test, which involves irradiating peripheral blood to induce hemolysis, is often positive and serves as a useful screening test. In CEP, 50%–70% of normoblasts in the bone marrow contain abundant porphyrins and fluoresce [108], but only a small proportion of peripheral erythrocytes fluoresce [109], probably because porphyrins leak from erythrocytes into the plasma due to hemolysis. In HEP, pink fluorescence is observed when urine is irradiated under long-wavelength UV light.

Histopathology reveals the deposition of PAS-positive material at the dermoepidermal junction and around dermal capillaries [37]. In PCT and HEP, subepidermal blisters can be observed.

TABLE 6 | Differential diagnoses of cutaneous porphyrias.

(1) Hereditary Xeroderma pigmentosum Hartnup disease (2) Metabolic Pellagra Iron deficiency anemia (3) Exogenous Drug-induced photosensitivity (4) Idiopathic Photodermatitis Polymorphous light eruption Solar urticaria Chronic actinic dermatitis Hydroa vacciniforme (5) Autoimmune disorders Bullous pemphigoid (6) Connective tissue diseases Systemic lupus erythematosus Systemic sclerosis (7) Others Pseudoporphyria

Direct immunofluorescence may show immunoglobulin deposition along vessel walls [110–112]. However, these histological features are non-specific. Given the skin fragility and impaired wound healing in patients with cutaneous porphyrias, skin biopsies should be avoided when possible [52].

8.1.2 | Biochemical Tests

The fundamental diagnostic principle of porphyrias is to demonstrate the accumulation of porphyrins or their precursors in vivo. Regarding subtype differentiation, it is recommended to measure erythrocyte protoporphyrin and coproporphyrin and urinary co-proporphyrin, Uporophyrin, PBG, and ALA [113] (CQ1). Based on which porphyrins or precursors are present in blood or urine, the subtype can be partially predicted (Table 7, Figure 2) [113, 114].

EPP is the most strongly suspected when erythrocyte protoporphyrin is elevated but urinary porphyrins remain within the normal range. Since protoporphyrin is excreted via bile into feces, urinary porphyrins typically remain within the reference range, whereas fecal protoporphyrin is markedly increased. XLP shows a similar pattern, with elevated erythrocyte protoporphyrin and normal urinary porphyrin levels, though levels are generally higher than in EPP [49, 88]. In HEP, erythrocyte protoporphyrin is also elevated, but plasma uroporphyrin levels are increased, and uroporphyrin and coproporphyrin are both detectable in urine.

When urinary porphyrins are positive, PCT is the most likely subtype. PCT is characterized by increased urinary uroporphyrin (isomer I > isomer III) [38], with urinary coproporphyrin also increased but never exceeding uroporphyrin. Urinary ALA and PBG levels remain normal, which distinguishes PCT from acute porphyrias with cutaneous symptoms, such as HCP and VP [37]. Erythrocyte porphyrins remain normal, but plasma uroporphyrin is markedly elevated [115]. The presence of urinary heptacarboxylporphyrin supports the diagnosis, as does the detection of fecal coproporphyrin and isocoproporphyrin, the latter being highly specific [38, 116]. However, the measurement of heptacarboxylporphyrin and fecal porphyrins is currently unavailable in commercial laboratories in Japan.

CEP is characterized by high concentrations of uroporphyrin I and coproporphyrin I erythrocytes [81], both of which are ex-creted in urine and feces. CEP is the only porphyria with abun-dant urinary type I porphyrins.

8.1.3 | Genetic Testing

Genetic testing is a powerful tool for confirming subtype diagnoses (CQ2). The identification of pathogenic variants in caustative genes provides a definitive diagnosis. Currently, all nine causative genes can be analyzed. Genetic testing is valuable for not only diagnostic confirmation, but also for identifying asymptomatic carriers within families, detecting presymptomatic cases of EPP and enabling a prenatal diagnosis [117–119]. In Japan, genetic testing for EPP is performed at the Department of Dermatology, Hirosaki University and the Kazusa DNA Research Institute.

TABLE 7 | Porphyrin and heme precursor profiles by porphyria type [113, 114].

|Porphyria type|Disease stage|Erythrocytes|Urine|Stool| |---|---|---|---|---| |AIP|Acute phase|N|ALA, PBG, UP, CP|UP>CP| |AIP|Latent phase|N|ALA, PBG|—| |ADP||PpIX|ALA, UP, CP|CP, PpIX| |VP|Acute phase|N, (PpIX)|ALA, PBG, UP, CP|PpIX>CP, XP| |VP|Latent phase|N|N|—| |HCP|Acute phase|N, (PpIX)|CPIII, ALA, PBG|CPIII| |HCP|Latent phase|N|N, (ALA, PBG)|CPIII| |PCT||N|UP>CP, 7P|CP>UP, isoCP| |HEP||PpIX|UP>CP, isoCP, 7P|isoCP| |CEP||UPI, CPI|UPI, CPI|UPI, CPI| |EPP||PpIX|N (CP)|PpIX| |XLP||PpIX|N|PpIX|

Note: Items in parentheses indicate those that may occasionally be elevated. Adapted from: Nakano [113, 114].

Abbreviations: 7P, heptacarboxylporphyrin; ALA, δ-aminolevulinic acid; CP, coproporphyrin; isoCP, isocoproporphyrin; N, normal; PBG, porphobilinogen; PpIX, protoporphyrin; UP, uroporphyrin; XP, X-porphyrin.

![graph TD\n A1[Photosensitivity] --> A2[Measure erythrocyte PpIX and CP]\n A2 -->|Increased CP| A3[Measure urinary CP and UP]\n A2 -->|Increased PpIX *| A4[Measure urinary CP and UP]\n A2 -->|Normal| A5[Measure urinary CP and UP]\n A3 -->|Increased| A6[CEP]\n A4 -->|Increased| A7[HEP]\n A4 -->|Normal| A8[EPP, XLP]\n A5 -->|Increased| A9[Measure urinary PBG and ALA]\n A5 -->|Normal| A10[Not cutaneous porphyria]\n A9 -->|Normal| A11[PCT]\n A9 -->|Increased **| A12[HCP, VP]\n](1/parseimages/figure9e7503d7685f4009808e7ca20af83373_0_4.png) In EPP, pathogenic variants in the FECH gene are usually identified, and the other allele carries the IVS3-48C polymorphism in most cases. Pathogenic variants in the CLPX gene can also cause EPP [35, 120], although cases have yet to be reported in Japan. Approximately 4% of patients with elevated protoporphyrin have no identifiable pathogenic FECH variant [121]. In such cases, possible explanations include XLP, EPP due to CLPX variants, or incomplete EPP caused by biallelic IVS3-48C.

Familial PCT is associated with heterozygous pathogenic variants in the UROD gene, but penetrance is low, and not all carriers develop symptoms. CEP is caused by pathogenic variants in the

UROS gene, although variants in the erythroid transcription factor GATA1 [45, 46] and occasionally in ALAS2 [47] have also been reported. Genetic testing of ALAS2 is essential for XLP, whereas a UROD analysis is diagnostic for HEP. To date, no Japanese cases of HEP with pathogenic variants have been reported.

8.2 | Acute Porphyrias

The accurate and early diagnosis of acute porphyrias begins with careful history-taking and a physical examination to raise clinical suspicion. Once an acute porphyria is suspected,

screening tests should be promptly performed. If abnormalities are detected, further biochemical and genetic testing is required to determine the specific subtype (Figure 3) [122].

8.2.1 | Screening Tests

The initial diagnostic step for acute porphyrias is the measurement of urinary ALA, PBG, and creatinine during an acute attack (CQ1). In all acute porphyrias, urinary ALA levels are markedly elevated, and in all but ADP, urinary PBG is also increased. During attacks, urinary ALA and PBG remain persistently elevated, typically at least five times the ULN. These elevations are sufficiently marked that spot urine samples are generally adequate, and 24-h collections are not required. To account for differences in urine concentrations, ALA and PBG should be normalized to creatinine (mg/g Cr). Given the magnitude of elevations during acute attacks, the measurement of urinary ALA and PBG alone is usually sufficient to confirm symptomatic acute porphyria. Although no universally accepted thresholds have been established, recent guidance from the American Gastroenterological Association suggests that urinary ALA or PBG > 10 mg/g Cr is diagnostic [122].

The timing of the measurement of urinary ALA and PBG is critical. In untreated patients, urinary ALA and PBG continue to rise for several days after symptom onset. In AIP, studies indicate that urinary ALA and PBG may remain elevated for months or even years after an attack [123]. However, values in HCP or VP may decline more rapidly. Intermittent testing of asymptomatic AIP carriers has shown normal urinary ALA and PBG levels in 15%–44% of cases [124, 125]. In HCP and VP, normal values during asymptomatic periods are equally or more common. Therefore, repeated testing during symptomatic attacks is necessary. In contrast, patients with frequently recurrent acute attacks usually have persistently elevated urinary ALA and PBG even between

![graph TD\n A1[Symptoms suggestive of acute porphyria] --> A2[Measure spot urine ALA and PBG with creatinine*]\n A2 -->|Urinary ALA/PBG >10 mg/g creatinine| A3[Definitive diagnosis of acute porphyria]\n A2 -->|Urinary ALA/PBG within normal range| A4[Not acute porphyria]\n A3 --> A5[Subtype diagnosis: biochemical and genetic testing]\n](1/parseimages/figure92e22c2dde7c41d5a7b495fbb19071a6_0_4.png) FIGURE 3 | Screening tests for acute porphyrias [122]. *Urinary ALA, PBG, and creatinine should be measured on spot urine during symptomatic episodes and repeated as needed; 24-hour urine collection is not required. ALA, δ-amiaminolevulinic acid; PBG, porphobilinogen. Adapted with permission from: Wang et al. [122].

attacks [103]. Thus, if a patient has recurrent symptoms suggestive of acute porphyria but urinary ALA and PBG are normal, acute porphyria is an unlikely cause.

Of note, a rapid and early diagnosis and treatment are crucial during acute attacks. However, the measurement of urinary ALA and PBG is not available in most clinical laboratories in Japan and often requires a referral to specialized centers, leading to delays of several days. The Watson-Schwartz test, a qualitative method for urinary PBG detection, was historically used for rapid screening [126], but is no longer widely available due to discontinued reagent supply.

8.2.2 | Biochemical Tests

If screening confirms acute porphyria, the next step is the biochemical testing of urine, feces, and erythrocytes to define the subtype (Figure 4) [127]. Specimens should be collected during the acute phase and, whenever possible, before the initiation of heme therapy. Distinct biochemical patterns for each subtype are summarized in Table 7 [113, 114, 128]. ADP can be distinguished by the absence of elevated urinary PBG and the presence of elevated erythrocyte protoporphyrin. AIP can be differentiated from other acute porphyrias by the absence of increased fecal porphyrins. In HCP, fecal coproporphyrin III is markedly elevated, while fecal protoporphyrin remains normal, distinguishing it from VP. VP is characterized by elevated fecal coproporphyrin and protoporphyrin, with the latter being predominant.

![graph TD\n A1[Symptoms suggestive of acute porphyria] --> A2[Urine ALA]\n A2 -->|Normal| A3[Not porphyria]\n A2 -->|Increased| A4[Urine PBG]\n A4 --> A5[ADP]\n A4 -->|Increased| A6[Fecal CP]\n A6 --> A7[AIP]\n A6 -->|Increased| A8[Fecal PpIX]\n A8 --> A9[HCP]\n A8 -->|Increased| A10[VP]\n](1/parseimages/figurefdb7198668d1411c9fbe050b1ec4a366_0_10.png) FIGURE 4 | Diagnostic algorithm for acute porphyrias [127]. ALA, δ-amiaminolevulinic acid; CP, Coproporphyrin; PBG, Porphobilinogen; PpIX, Protoporphyrin; UP, Uroporphyrin. Adapted with permission from: Daimon [127].

Importantly, urinary porphyrins alone should not be used for screening acute porphyrias. Mild, non-specific elevations are common in secondary porphyrinuria and may lead to a misdi-agnosis if interpreted without ALA and PBG.

8.2.3 | Genetic Testing

Genetic testing is indicated for patients with a biochemical diagnosis of acute porphyria to confirm the subtype (CQ2). At present, genetic testing is not recommended as an initial screening tool in the absence of biochemical evidence. Four causative genes have been identified: HMBS, ALAD, PPOX, and CPOX. Comprehensive sequencing detects pathogenic variants in 95%–99% of cases. In Japan, AIP, VP, and HCP were added to the list of disorders eligible for the reimbursement of genetic testing under the 2022 revision of the national health insurance system. Genetic testing for these genes is currently available at the Kazusa DNA Research Institute.

Most genetic carriers of acute porphyria remain asymptomatic throughout life [95]. Thus, asymptomatic carriers may be present within affected families. Once a pathogenic variant is identified in a proband, genetic counseling is essential to inform family members of the disease and its genetic background. The genetic testing of asymptomatic relatives is recommended as awareness of the carrier status can help avoid precipitating factors and prevent exposure to porphyrinogenic drugs.

9 | Complications

9.1 | Cutaneous Porphyrias

The overall prognosis of cutaneous manifestations in porphyrias is generally favorable with appropriate photoprotection. However, repeated sun exposure can cause irreversible damage, such as loss of the nasal tip, auricles, or digits. Other complications include anemia and hepatic dysfunction, the latter of which may progress to liver failure and result in a poor prognosis. In addition, although rare, neurodevelopmental disorders and seizures have been reported in EPP and HEP, warranting clinical vigilance [75, 92, 93].

9.1.1 | Hepatic Dysfunction

Hepatic dysfunction is the most important complication in EPP, occurring in 25%–51.6% of cases [129, 130]. Choleithiasis develops in approximately 20% of patients [75]. When hepatic involvement progresses, jaundice and fatigue may occur. Elevated serum transaminases levels are observed in about 30% of cases, with a few progressing to liver failure. Liver transplantation has improved the long-term survival of patients with EPP-related liver failure; however, because excess protoporphyrin production from the bone marrow persists, recurrent hepatic dysfunction is common, and re-transplantation has been required in some cases.

In PCT, hepatic dysfunction is also a characteristic complication, whereas neurological symptoms are not observed. Hepatic findings range from non-specific steatosis to cirrhosis and HCC

[131]. The incidence of cirrhosis and HCC is higher in PCT than in other hepatic porphyrias [129]. Although chronic HCV infection and other cofactor's may contribute, the precise mechanisms remain unclear. Notably, the severity of cutaneous lesions does not necessarily correlate with the degree of hepatic impairment [131]. XLP is also associated with hepatic dysfunction, with a higher incidence and greater severity than in EPP [132, 133]. Hepatic dysfunction may also occur in HEP.

9.1.2 | Anemia

In EPP, microcytic hypochromic anemia is sometimes observed, with a reported prevalence of 21%–51.8% [76, 129, 130]. In PCT, iron overload is common, with elevated serum iron and ferritin levels. While blood transfusion may be useful in cases of severe anemia, iron supplementation can exacerbate symptoms and, thus, should be used with caution.

CEP is characterized by hemolytic anemia proportional to the degree of UROS deficiency, and hemolysis may be present from the fetal period. Clinical severity ranges from mild cases with compensated erythroid hyperplasia in the bone marrow to severe transfusion-dependent anemia [130, 134]. Patients with onset before 5 years old are at a high risk of severe, progressive hematologic manifestations, such as neonatal jaundice, transfusion-dependent hemolytic anemia, thrombocytopenia, and splenomegaly [79]. Secondary hypersplenism can lead to pancytopenia, and the prognosis depends on the severity of anemia, bleeding tendency, and susceptibility to infections [135]. In contrast, patients who develop mainly cutaneous symptoms after 10 years old often show no clinically significant hematologic abnormalities [79]. Hematologic complications are a major predictor of a poor prognosis in CEP [79].

In HEP, anemia occurs in more than 50% of cases [90]. It is often hemolytic and frequently associated with splenomegaly.

9.2 | Acute Porphyrias

In recent years, complications beyond neurological dysfunction have been recognized more frequently in acute porphyrias, particularly HCC and KD. Therefore, a regular evaluation and long-term monitoring are essential for patient management.

9.2.1 | HCC

The association between AIP and HCC was first reported in 1984, and subsequent studies have estimated the relative risk and standardized incidence ratio of HCC in patients with acute porphyrias [136–141]. A nationwide Norwegian cohort study reported an annual HCC incidence of 0.35% in acute porphyria patients, with an adjusted hazard ratio of 108 (95% confidence interval [CI]: 56–207) compared with non-porphyria controls [142]. Similarly, a Swedish cohort study using data from 1244 patients in the national porphyria registry showed an adjusted hazard ratio of 38 (95% CI: 24.3–59.3) [104]. In Japan, retrospective cohort studies using large-scale clinical databases also found a high frequency of liver fibrosis, cirrhosis, and HCC in patients with acute porphyrias [101].

Proposed mechanisms for hepatocarcinogenesis include ALA-induced oxidative stress, hepatocyte apoptosis, deoxyribo-nucleic acid (DNA) damage, mitochondrial dysfunction, and changes in the expression of tumor-associated proteins [134].

Most studies report that the average age at the HCC diagnosis exceeds 60 years old. Elevated urinary PBG levels and a history of hospitalization for acute attacks have been associated with an increased HCC risk [104]. Patients with acute porphyrias over 50 years old with a history of acute attacks may benefit from annual HCC screening to enable early detection. Although the risk in clinically asymptomatic patients with persistently elevated porphyrin precursors remains uncertain, it should not be overlooked.

9.2.2 | CKD

Symptomatic patients with acute porphyrias are more likely than latent carriers to develop chronic renal impairment, sometimes referred to as porphyria-associated kidney disease (PAKD) [105]. This decline in kidney function progresses gradually and appears to involve multiple pathogenic factors [143]. The main mechanism is thought to be the direct nephrotoxicity of porphyrin precursors. Excess ALA, a potent oxidant, reacts with intracellular iron and enzymes to generate superoxide and hydroxyl radicals, leading to oxidative stress, mitochondrial damage, and dysfunction [144, 145]. Several studies have confirmed ALA-induced oxidative injury to mitochondria [146–148]. In vitro studies using renal epithelial cells have shown that ALA and PBG induce apoptosis, autophagy, endoplasmic reticulum stress, inflammation, fibrosis-promoting factors, and changes in adhesion molecules [105]. Histological findings from the renal biopsies of patients with acute porphyrias show chronic tubulointerstitial injury [105, 149–151].

ALA also exerts vasoconstrictive effects and can induce vascular spasm during acute attacks. Chronic exposure may lead to renal vasospasm, vascular narrowing, ischemia, and, ultimately, glomerulosclerosis, as demonstrated in kidney biopsy specimens [105, 149]. Additional contributors may include hypertension, electrolyte disturbances (particularly hypona-tremia), and dehydration during acute attacks, all of which place additional stress on the kidneys. Hypertension is com-mon in acute porphyria patients, and long-standing hypertension can exacerbate renal vascular injury and CKD. However, a French observational study demonstrated that a history of acute attacks correlated with gradual CKD progression in AIP patients, independent of hypertension [134], suggesting that PAKD and hypertensive nephroscclerosis represent distinct but important risk factors.

While the prevalence of CKD does not appear to be higher in asymptomatic carriers than in healthy individuals, specific variants of peptide transporter 2, which functions as an ALA transporter in proximal renal tubules, have been shown to strongly affect the severity of CKD in AIP patients, even in the absence of symptoms [152]. Thus, PAKD should be considered in asymptomatic carriers who develop unexplained CKD.

10 | Differential Diagnoses

10.1 | Cutaneous Porphyrias

10.1.1 | Subtype Differentiation

A broad range of photodermatoses and disorders exacerbated by light exposure should be considered in the differential diagnosis (Table 6) [113]. Differentiation from other porphyrias with cutaneous manifestations is always necessary [153]. In addition, iron deficiency anemia can show mildly elevated erythrocyte protoporphyrin levels, approximately 150 µg/dL RBC, and should be included in the differential diagnosis [154].

XLP and EPP cannot be distinguished based on clinical grounds alone. Both disorders show elevated erythrocyte protoporphyrin levels; however, in EPP, the majority is free protoporphyrin, whereas free and zinc-bound protoporphyrin both are elevated in XLP. In Japan, the measurement of free protoporphyrin is not commercially available, and therefore, genetic testing is required for differentiation.

The cutaneous findings of PCT should be differentiated from those of HCP and VP. PCT is not associated with elevated urinary ALA. When cutaneous lesions of PCT become severe, they may be difficult to distinguish from those of CEP. In particular, secondary CEP can present with cutaneous manifestations and urinary porphyrin profiles resembling those of PCT [155]. CEP is differentiated by markedly elevated erythrocyte porphyrin concentrations.

10.1.2 | Secondary Porphyrias

In cases of late-onset EPP, secondary EPP associated with myelodysplastic syndrome (MDS) and related disorders should be considered [156]. This condition results from abnormal clones of erythroid progenitor cells in the bone marrow carrying variants in the FECH gene or the loss of chromosome 18, which contains the FECH gene. Since these are acquired genetic or chromosomal abnormalities, pathogenic FECH variants are not detected in germline DNA; however, a bone marrow analysis may clarify the etiology [157]. Secondary CEP associated with MDS has also been described [158]. In these disorders, if the underlying hematologic disease improves, photosensitivity may improve or even resolve.

10.1.3 | Pseudoporphyria

Pseudoporphyria is an important differential diagnosis of PCT (Table 8, CQ8). Its clinical manifestations closely resemble those of PCT, but porphyrin levels are within the normal range or only slightly elevated [159]. The main causes are chronic hemodialysis and medication use, although cases following tanning salon exposure have been reported [160]. Many different drugs have been implicated, and imatinib has recently been recognized as an increasingly important trigger.

TABLE 8 | Causes of pseudoporphyria.

|Category|Examples| |---|---| |Ultraviolet exposure|PUVA; tanning beds; prolonged sun exposure| |Drugs|Molecularly targeted agents (imatinib, sunitinib); NSAIDs (diclofenac, ketoprofen, naproxen, diflunisal, rofecoxib); antiarrhythmics (amiodarone); diuretics (torsemide, furosemide); oral hypoglycemic agents (metformin); antibacterials (ciprofloxacin, tetracycline, nalidixic acid, β-lactams); antifungals (voriconazole); immunosuppressants (cyclosporine); sulfa drugs (dapsone); vitamins (pyridoxine); psoriasis therapies (psoralen)| |Others|Chronic renal failure; hemodialysis; chlorophyll; brewer's yeast; Coca-Cola|

10.2 | Acute Porphyrias

10.2.1 | Subtype Differentiation

A diagnostic algorithm for acute porphyrias is shown in figure 4 [127]. In patients with suspected acute porphyria based on symptoms and positive results in biochemical screening, the measurement of fecal porphyrins is useful for subtype differentiation.

ADP is distinguished from other acute porphyrias by the absence of elevated urinary PBG levels. AIP is differentiated by normal fecal porphyrin excretion. HCP is characterized by markedly increased fecal coproporphyrin III without a corresponding increase in protoporphyrin, which distinguishes it from VP. The presence of elevated fecal protoporphyrin supports the diagnosis of VP. However, as commercial testing for fecal porphyrins is currently unavailable in Japan, genetic testing is required for definitive subtype determination.

10.2.2 | Secondary Porphyrinuria

(Coproporphyrinuria)

When urinary porphyrins, rather than porphyrin precursors, such as ALA and PBG, are used for screening, there is a risk of a misdiagnosis. This is because certain diseases, drugs, or chemical exposure can cause mild-to-moderate elevations in urinary porphyrins, particularly coproporphyrin I and III, which are unrelated to primary porphyrias [161, 162]. These conditions represent broader disturbances in porphyrin metabolism and are classified as secondary porphyrinuria (coproporphyrinuria) (Table 9 [113], CQ8). In some hepatobiliary disorders, the decreased biliary excretion of porphyrins leads to secondary increased urinary coproporphyrin [163]. Alcohol consumption

TABLE 9 | Porphyrinuria (coproporphyrinuria) [113].

|Category|Examples| |---|---| |Inborn errors of metabolism|Hereditary tyrosinemia; Dubin-Johnson syndrome; Rotor syndrome| |Hepatobiliary diseases|Obstructive jaundice; cholestasis; alcoholic liver disease; acute hepatitis; chronic hepatitis; cirrhosis; primary biliary cholangitis; hepatocellular carcinoma| |Hematologic diseases|Iron deficiency anemia; pernicious anemia; hemolytic anemia; malignant lymphoma; leukemia| |Metabolic diseases|Diabetes mellitus; hyperthyroidism; vitamin B2 deficiency; vitamin B6 deficiency; niacin deficiency| |Chemical exposures|Lead; arsenic; mercury; halogenated aromatic compounds (e.g., PCBs, dioxins); allyl-containing compounds; phenobarbital; carbamazepine; oral contraceptives; alcohol; trichloroethylene|

Note: Adapted from: Nakano [113].

and CYP-inducing drugs can inhibit the organic anion transporters responsible for the biliary excretion of porphyrins, thereby increasing urinary elimination [164, 165].

Secondary porphyrinuria can be distinguished from acute porphyrias by confirming that urinary ALA and PBG remain within normal limits or are only slightly elevated. However, special attention is required in cases of lead poisoning and hereditary tyrosinemia, in which urinary ALA is elevated and clinical features may resemble those of acute porphyrias [166].

10.2.3 | Lead Poisoning

Excess lead exposure inhibits the activity of ALAD, the enzyme deficient in ADP [167]. As a result, urinary ALA is elevated, while PBG remains within the normal range, resulting in similar biochemical findings to those of ADP. Clinically, symptoms may develop over several weeks and include personality changes, headache, abdominal pain, vomiting, constipation, weakness, and sensory disturbances, such as numbness. Unlike acute porphyrias, however, peripheral neuropathy with external muscle weakness leading to wrist drop is characteristic. The measurement of blood lead concentrations allows differentiation from acute porphyrias.

10.2.4 | Hereditary Tyrosinemia

Hereditary tyrosinemia is an autosomal recessive disorder of tyrosine catabolism caused by pathogenic variants in the fumary-lacetoacetate hydrolase (FAH) gene. A deficiency of FAH leads to

the hepatic accumulation of fumarylacetoacetate and succinylacetone, both of which inhibit ALAD [168]. Biochemical testing shows elevated urinary ALA with normal PBG levels. Clinically, hereditary tyrosinemia typically manifests in infancy or early childhood, whereas acute porphyrias rarely present before puberty [169].

11 | Treatment and Prevention

11.1 | Cutaneous Porphyrias

11.1.1 | Photoprotection

Nearly all cutaneous manifestations of porphyrias are attributable to photosensitivity; in the absence of light exposure, these symptoms do not occur. Therefore, photoprotection is the cornerstone of preventive management across all subtypes. Porphyrins exhibit an absorption peak around 405 nm, with a smaller, broader peak between 580 and 680 nm in the visible spectrum. Since light within these ranges penetrates window glass and is present in artificial indoor light sources, comprehensive photoprotection must account for both natural and artificial light exposure.

Outdoor protection measures include wide-brimmed hats and sun-protective clothing. Sunscreens are useful when they contain physical scattering agents, such as zinc oxide or iron oxide, with spectral coverage matching porphyrin absorption wavelengths (CQ5). Photosensitivity can also be triggered by artificial light sources; prolonged surgical procedures under surgical lamps have been reported to cause skin burns and even intestinal injury [170, 171]. Filters that remove the principal absorption wavelengths of porphyrins should be considered (CQ7). Similarly, light exposure through car windows requires attention.

Vitamin D deficiency has been reported in approximately 50% of EPP patients due to strict photoprotection [172]. The regular monitoring of serum 25-hydroxyvitamin D levels is recommended, with supplementation or dietary therapy as needed (CQ10). In some cases of EPP, limited and controlled light exposure may induce pigmentation and confer a “hardening effect”, thereby enhancing tolerance to sunlight. Therefore, controlled exposure may be considered in select patients who can tolerate brief light exposure [173, 174].

Acute cutaneous manifestations can be treated with topical corticosteroids for erythema and topical antibiotics for erosions. In chronic cutaneous manifestations, no curative treatment is currently available; thus, prevention remains the mainstay of management. Subtype-specific treatment strategies are outlined below:

11.1.2 | Subtype-Specific Management

11.1.2.1 | EPP. Traditionally, in addition to photoprotection, oral β-carotene has been used based on the hypothesis that its cutaneous deposition reduces the transmission of sunlight into the dermis [175, 176]. However, in Japan, β-carotene

is approved only as a food additive, not as a therapeutic agent, and oral administration for therapeutic purposes is not recommended (CQ6). Small studies have suggested the potential benefit of cimetidine [177] or combination therapy with cimetidine and lactulose [178] for cutaneous and hepatic manifestations, but both remain off-label and require careful consideration (CQ4).

Severe anemia may require transfusion, but iron supplementation should be avoided as it may exacerbate symptoms (CQ9). Hepatic dysfunction should be managed with hepatoprotective agents, such as glycyrrhizin or ursodeoxycholic acid (UDCA) [179] (CQ4). In cases progressing to liver failure, liver transplantation has extended survival. However, because excess protoporphyrin production from bone marrow persists, the recurrence of hepatic dysfunction and the need for re-transplantation have been reported [180]. Sequential bone marrow transplantation following liver transplantation is considered the ideal approach.

Although not approved in Japan, afamelanotide, a melanocortin-1 receptor agonist administered as a subcutaneous implant, has been approved in Europe and the United States [181]. Afamelanotide promotes pigmentation and exerts anti-inflammatory and anti-fibrotic effects [182]. In Japan, der-simelagon (MT-7117), an oral selective melanocortin-1 receptor agonist, is undergoing phase 3 international clinical trials for EPP and XLP [182]. Unlike acute porphyrias, EPP and XLP do not require the avoidance of drugs known to precipitate acute attacks [53] (Table 3) [7].

11.1.2.2 | PCT. In addition to photoprotection, management includes the elimination of precipitating factors such as viral hepatitis, alcohol consumption, or medications. Phlebotomy is an effective therapeutic option (CQ3), particularly in patients with iron overload [183]. Typically, 300–500 mL of blood is removed every 2–3 weeks until the following targets are reached: hemoglobin is 10–11 g/dL, serum iron 50–60 µg/dL, urinary uroporphyrin 50–100 µg/day, and serum ferritin 15–20 ng/mL. As the normalization of porphyrin levels may require 6–12 months, photoprotection should be maintained during this period.

Approximately 60% of patients with PCT have concurrent HCV infection [15]. With the advent of direct-acting antiviral agents, a sustained virologic response has become achievable [184], and the eradication of HCV has been associated with PCT remission [185, 186]. Combalia et al. reported an improvement in skin lesions and the normalization of urinary porphyrins in 16 patients with active PCT resistant to phlebotomy following antiviral therapy [187].

In Europe and the United States, low-dose hydroxychloroquine (100 mg twice weekly) or chloroquine (125 mg twice weekly) is also used [188, 189]. These agents enhance the urinary excretion of hepatic porphyrins. They are particularly suitable for patients for whom plebotomy is contraindicated (e.g., those with severe anemia or advanced cardiac disease). Iron chelation therapy [190] and cimetidine [191, 192] have also been reported as effective. Iron supplementation should be avoided as it may worsen PCT.

PCT responds well to initial treatment in about 90% of cases [15], but relapses can occur. Continued alcohol consumption and

smoking are risk factors for relapse [15]. Estrogen therapy may precipitate PCT; however, after remission, transdermal estrogen replacement therapy has been reported to be safe [193]. The regular monitoring of urinary uroporphyrin levels is recommended for the early detection of recurrence.

11.1.2.3 | CEP. In CEP, strict photoprotection of the skin and eyes is essential. Patients should avoid trauma to fragile skin because irreversible sequelae, such as digital loss or contractures, may require surgical intervention. Ocular involvement can be prevented by wearing sunglasses that block UV to visible wavelengths. Infections, such as corneal ulcers, scleritis, or blepharitis, are treated with antibiotic eye drops or ointments. In cases of ectropion, corrective surgery may be necessary [87]. Beta-carotene has been used, but a study by Badminton et al. reported benefits in only 2 of 12 patients, with treatment discontinued in 6 due to ineffectiveness [194].

Hemolytic anemia and associated bone marrow hyperplasia are effectively treated with blood transfusion, which suppresses porphyrin production. However, long-term transfusion carries a risk of iron overload, leading to cirrhosis, nephrotic syndrome, or cardiac dysfunction [87]. An increased transfusion frequency may be required due to hypersplenism or alloimmunization [170]. Splenectomy can improve anemia and photosensitivity in select cases, but does not provide the long-term control of porphyrin overproduction [195]. Vitamin D supplementation is recommended to prevent bone demineralization, and bisphosphonates may be considered for osteoporosis [87]. The only curative therapy is bone marrow transplantation, which can resolve both photosensitivity and anemia. Over 20 successful cases have been reported, with some achieving long-term remission beyond 20 years [196]. However, severe complications, such as graft-versus-host disease, hepatic failure, and sepsis, have also been reported [196].

In neonates suspected of CEP with jaundice, phototherapy should be avoided because it may exacerbate photosensitivity; conservative management is preferred [87, 197]. Similar precautions are required in infants born to mothers with CEP, even if the child does not carry the pathogenic variant, as the placental transfer of maternal porphyrins may transiently increase photosensitivity [87, 198].

11.1.2.4 | XLP. Treatment follows the same principles as EPP. However, in contrast to EPP, iron supplementation may lower protoporphyrin levels and improve symptoms in XLP [53] (CQ9). This effect is thought to result from adequate substrate availability, allowing FECH to enhance the incorporation of iron into protoporphyrin to heme [199, 200].

11.1.2.5 | HEP. HEP often causes marked photosensitivity, which can result in extensive skin damage and digital loss; therefore, strict photoprotection, including the avoidance of UVA exposure, is essential. In contrast to PCT, phlebotomy and chloroquine are usually ineffective because iron overload is typically absent [201]. Nonetheless, isolated case reports describe clinical and biochemical improvement with chloroquine or phlebotomy [118]. Precipitating factors known to trigger PCT, such as iron overload, estrogen therapy, and CYP-inducing drugs, should also be avoided [202].

11.2 | Acute Porphyrias

There are four types of acute porphyria, but the management of acute attacks and their prevention is largely shared across subtypes. Accordingly, recommendations are presented collectively, without subtype stratification. (The management of cu- taneous manifestations is described in the section on cutaneous porphyrias).

11.2.1 | Treatment

11.2.1.1 | Avoidance of Triggers. As noted in the Etiology/Pathophysiology section, acute porphyrias require both a genetic predisposition as well as precipitating factors. The same principle applies to recurrence: if a trigger persists during an attack, the trigger should be immediately removed. Known precipitiants are summarized in Table 3 [7, 96, 203, 204]; among them, drugs are particularly important [205] (CQ8). Medications used to treat attack symptoms can themselves exacerbate an attack and, therefore, careful selection is essential. More than 1000 drugs have been implicated as potential precipitants [206]. In addition to the representative agents listed in Table 3 [7, 207], clinicians should consult up-to-date online drug safety resources, including the International Porphyria Network Drug Database, the American Porphyria Foundation Drug Database, the Welsh "Drugs in Porphyria" service, and the Porphyria Drug List.

11.2.1.2 | Acute Attack (Hemin Therapy). Intravenous hemin is considered the most effective treatment for acute attacks (CQ12). Although large double-blind randomized trials are lacking, evidence from small randomized trials and multiple observational studies supports its efficacy [6, 96, 208]. Two formulations are available: heme arginate (Normosang; available in Japan and Europe) and hematin (Panhematin; available in the United States). Exogenous heme is taken up by the liver, replenishes the depleted hepatic heme pool, and down-regulates ALAS1, thereby reducing precursor production [6, 208]. The recommended dose is 34 mg/kg/day by intravenous infusion (insurance coverage in Japan: 3 mg/kg/day for 4 consecutive days; maximum 250 mg/day). Reported response rates are approximately 70%–80% [96, 209], and earlier administration after symptom onset is associated with better outcomes [96]. Adverse effects include phlebitis and vasculitis [6, 96, 208]. With higher cumulative exposure, iron overload can occur and should be monitored [208].

11.2.1.3 | Glucose Administration. High-dose glucose suppresses ALAS1 and reduces porphyrin precursors, and may be effective for mild attacks [6, 208]. Since the ALAS1-suppressive effect is modest, intravenous hemin therapy is required for moderate to severe attacks, with glucose being used as an adjunct. Reported regimens typically use 300–500g of glucose per day [6]. Such high doses are difficult to achieve via peripheral infusion; when central access is not available, the maximum feasible amount should be given with careful monitoring of the fluid balance and electrolytes to prevent complications [6, 208].

11.2.1.4 | Cimetidine. Cimetidine inhibits CYP enzymes and is thought to indirectly suppress ALAS1 [6]. Evidence for its efficacy in acute attacks is limited, consisting mainly of case

reports and small observational studies, and robust proof is lacking. Its use is off-label and should be undertaken with caution in Japan.

11.2.1.5 | Symptomatic Management. During attacks, patients may present with severe abdominal pain accompanied by various other manifestations, including nausea/vomiting, hypertension, tachycardia, electrolyte abnormalities (notably hyponatremia), peripheral neuropathy, consciousness disturbance, and seizures. While hemin and glucose therapies generally improve these symptoms, targeted symptomatic management is also required.

$\bullet$ Abdominal pain: Often extreme and requires prompt control. Mild pain may respond to acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), whereas severe pain frequently necessitates opioid analgesics. Morphine, buprenorphine, and fentanyl are considered to be safe. Early intravenous hemin therapy is crucial. Scopolamine butylbromide (hyoscine butylbromide) and pentazocine should be avoided.

$\bullet$ Nausea and vomiting: Prochlorperazine and ondansetron are considered to be safe. Since evidence regarding metocpramide remains conflicting, its use should be avoided.

$\bullet$ Hypertension: Common during attacks and in the long term, and often associated with CKD. Treatment follows standard practice; many antihypertensive agents are considered to be safe [210], including calcium channel blockers (amlodipine, nifedipine, and nimodipine); angiotensin II receptor blockers (valsartan, telmisartan, losartan, irbesartan, and candesartan; angiotensin-converting enzyme inhibitors (ramipril, perindopril, lisinopril, enalapril, and captopril); β-blockers (atenolol, bisoprol, carvedilol, labetalol, metoprolol, pindolol, propranolol, and sotalol); α1-blockers (doxazosin, prazosin, and terazosin); and loop diuretics (furosemide).

$\bullet$ Peripheral neuropathy: A hallmark of acute porphyria that can progress to quadriparesis or respiratory failure. Prompt and appropriate intravenous hemin therapy is the most important intervention and has been associated with neurological improvement [96]. As recurrence prevention improves (e.g., with givosiran), clinical outcomes may further improve. Neuropathic pain can be treated with gabapentin or pregabalin [211].

$\bullet$ Seizures: Manage acutely with diazepam. Levetiracetam, lacosamide, lamotrigine, and gabapentin are regarded as safe options for antiepileptic therapy. Carbamazepine, phenytoin, and phenobarbital should be avoided [6]. Propofol or midazolam may be used for status epilepticus requiring deep sedation.

* Photosensitivity (HCP/VP): Manage primarily with photo-protection. Conventional sunscreens are often insufficient; formulations containing zinc oxide or titanium dioxide are preferred, and physical barriers are the most effective [212]. The preventive efficacy of givosiran for cutaneous photo-sensitivity has not yet been established.

11.2.2 | Prevention

As in the management of acute attacks, the avoidance of precipitating factors is central to prevention. Lifestyle guidance should be provided to help patients identify and eliminate potential triggers. Female sex hormone preparations can precipitate attacks and should be avoided. In women with catamenial attacks, gonadotropin-releasing hormone analogs may be considered to suppress ovulation and prevent recurrence [6, 96].

11.2.2.1 | Intermittent Heme Prophylaxis. Some patients receive intermittent intravenous hemin infusions during attack-free intervals (e.g., every 1–2 weeks). This preventive strategy may be considered for patients experiencing frequent or unpredictable attacks and has shown potential benefits in reducing attack frequency [6, 208]. However, long-term administration carries risks, such as phlebitis (with the subsequent loss of venous access) and iron overload [6, 208]. Since this approach is off-label in Japan, it should be undertaken with careful clinical judgment and close monitoring.

11.2.2.2 | Givosiran. Givosiran is an RNA interference (RNAi) therapy that selectively degrades hepatic ALAS1 mRNA, thereby suppressing ALAS1 expression and reducing the levels of ALA and PBG, ultimately preventing attacks [213] (CQ13).

In the phase 3 randomized, double-blind ENVISION trial, givosiran significantly reduced the annualized attack rate compared with placebo, decreased urinary ALA and PBG levels, and reduced hemin use and daily pain scores during the blinded period [214]. In the 30-month open-label extension, these effects were maintained; patients who crossed over from placebo achieved similar clinical and biochemical benefits, including reductions in urinary ALA and PBG, after starting givosiran [215]. Based on these findings, givosiran has been available in Japan since 2021 and is currently regarded as the most effective option for attack prevention. The recommended dose is 2.5 mg/kg administered subcutaneously once monthly.

Reported adverse events include injection-site reactions, nausea, fatigue, and elevations in hepatic enzymes and renal function markers; no treatment-related deaths were observed [214]. Potential long-term concerns include renal dysfunction [213] and hyperhomocysteinemia [216], underscoring the need for on-going monitoring.

11.2.2.3 | Liver Transplantation. Liver transplantation is the only definitive therapy that can potentially cure acute porphyrias [6, 208]. Reports on severely affected patients demonstrate the normalization of ALA and PBG levels and the complete elimination of attacks following transplantation. In a cohort of 38 patients with AIP, 9 deaths (24%) occurred over an approximately 16-year follow-up. One- and 5-year survival rates were 92% and 82%, respectively, which are comparable to those for liver transplantation performed for other metabolic disorders. Peripheral neuropathy-related neurological symptoms also improved after transplantation [217]. However, limitations include donor organ scarcity, surgical invasiveness, lifelong immunosuppressive therapy, and a relatively high incidence of hepatic artery thrombosis [218]. Therefore, liver

transplantation is reserved for a small subset of patients with life-threatening or medically refractory disease [208, 217].

12 | CQs

Table 10 summarizes the CQs included in these guidelines together with their corresponding recommendation grades.

CQ1. Is the measurement of porphyrins and their precursors useful for a subtype diagnosis?

Grade of recommendation: C1.

Level of evidence: IV.

Recommendation: As a screening test, the measurement of porphyrins and their precursors is useful in patients with acute abdominal pain or photosensitivity to determine whether porphyria is present.

Explanation: In the diagnosis of porphyria, demonstrating the accumulation of porphyrins or their precursors in the body is fundamental. When porphyria is suspected based on clinical features such as acute abdominal pain or photosensitivity, a laboratory evaluation should include measurements of erythrocyte protoporphyrin, erythrocyte coproporphyrin, and creatinine in

blood, as well as urinary coproporphyrin, uroporphyrin, PBG, and ALA [113].

In cutaneous porphyrias, the detection of erythrocyte protoporphyrin or coproporphyrin suggests EPP, XLP, CEP, or HEP (Figure 2). Conversely, if erythrocyte porphyrins are normal but urinary coproporphyrin and uroporphyrin are elevated, PCT or HCP with cutaneous manifestations, or VP with cutaneous manifestations, should be suspected. Although no studies have specifically evaluated the sensitivity or specificity of erythrocyte protoporphyrin or coproporphyrin levels for differentiating cutaneous porphyrias, a 20-year review from the Cardiff Institute reported elevated erythrocyte protoporphyrin levels in all 424 patients diagnosed with EPP [219]. Likewise, in all 457 patients with PCT, elevations in urinary uroporphyrin and heptacarboxylporphyrins were observed [219]. However, the measurement of heptacarboxylporphyrins and fecal porphyrins is not currently available in clinical laboratories in Japan.

Elevated urinary PBG is a characteristic finding of acute porphyrias, except for ADP [15]. In suspected acute porphyrias, the measurement of ALA, PBG, and creatinine in a spot urine sample collected during an acute attack is recommended. A diagnosis of acute porphyria can be established if urinary ALA or PBG exceeds 10 mg/creatinine [122] (Figure 3) [7]. Once acute porphyria is confirmed, further testing is required to distinguish AIP, HCP, and VP (Figure 4) [37, 52, 53]. The measurement of

TABLE 1 | Clinical questions (CQs) and grades of recommendation.

|CQ No.|Clinical question|Grades of recommendation| |---|---|---| |1|Is the measurement of porphyrins and their precursors useful for subtype diagnosis?|C1| |2|Is genetic testing useful for subtype diagnosis of porphyrias?|B| |3|Is therapeutic phlebotomy effective in the management of porphyria cutanea tarda (PCT)?|B| |4|Is treatment with cimetidine, cimetidine combined with lactulose, or ursodeoxycholic acid effective for hepatic impairment in erythropoietic protoporphyria (EPP)?|C1| |5|Is photoprotection (use of sunscreens) effective in the prevention of cutaneous porphyrias?|C1| |6|Is the oral administration of beta-carotene effective for the prevention of erythropoietic protoporphyria (EPP)?|C2| |7|Is shielding from light in the surgical field effective during surgical procedures involving thoracotomy or laparotomy?|B| |8|Is reviewing a patient's medication history useful in the management of porphyrias?|B| |9|Is iron supplementation effective for anemia in erythropoietic protoporphyria (EPP)?|C2| |10|Is active vitamin D supplementation effective for vitamin D deficiency and osteoporosis in patients with erythropoietic protoporphyria (EPP)?|C1| |11|Is the erythrocyte protoporphyrin level associated with hepatic impairment in erythropoietic protoporphyria (EPP)?|B| |12|Should hemin preparations be administered promptly during acute attacks of acute porphyrias?|B| |13|Should givosiran be administered to patients with acute porphyria?|A|

Note: CQ, clinical question; grades of recommendation: A, strongly recommend; B, recommend; C1, recommended as one option; C2, not recommended (insufficient evidence); D, recommend against.

fecal porphyrins is necessary for subtype differentiation; however, as mentioned above, this test is currently unavailable in Japan.

It should also be noted that urinary porphyrin levels may be elevated in conditions other than porphyria [161, 162] (Table 9) [113], and thus, the specificity and sensitivity of this test are limited. Therefore, urinary porphyrin levels alone are insufficient to provide a definitive basis for subtype differentiation. Ultimately, for both cutaneous and acute porphyrias, final confirmation of the subtype diagnosis requires genetic testing, as described in the following section [219].

CQ2. Is genetic testing useful for a subtype diagnosis of porphyrias?

Grade of recommendation: B.

Level of evidence: IV.

Recommendation: Genetic testing is useful for making a differential diagnosis among the various types of porphyrias.

Explanation: Although initial screening using blood or urine to measure porphyrin precursors has a certain degree of utility, genetic testing is particularly valuable in cases where clinical symptoms are non-specific or when precursor levels are not elevated, making differentiation among porphyrias challenging [153].

The reported sensitivities of genetic testing are high: 98.1% for HMBS in AIP, 96.9% for CPOX in HCP, and 100% for PPOX in VP [153, 220]. The diagnostic sensitivity for EPP due to FECH deficiency is also high at 93.9% [221].

In porphyrias, pathogenic variants comprise not only point variants, but also large deletions encompassing multiple exons. In such cases, direct sequencing alone may be insufficient, and gene dosage analyses, such as Multiplex Ligation-dependent Probe Amplification, are required [222, 223]. In EPP, it is well established that the combination of a pathogenic FECH variant and the intronic polymorphism IVS3-48C in the trans allele leads to reduced FECH activity, which plays an important role in disease manifestation. Notably, the prevalence of this polymorphism differs among populations: 11% in Europeans, 2.7% in North Africans, and 43% in Japanese individuals [224]. Therefore, if direct sequencing fails to detect a pathogenic variant, a targeted analysis of this polymorphic hotspot is also essential.

However, certain caveats must be considered when performing genetic testing for porphyrias. First, failure to detect a pathogenic variant in the target gene does not definitively exclude the diagnosis. Second, in autosomal dominant porphyrias with low penetrance, the identification of a pathogenic variant does not necessarily correlate with clinical manifestations when the trans allele does not harbor a disease-causing polymorphism [95, 225].

Thus, genetic testing is a useful tool for not only confirming the diagnosis in affected patients but also estimating recurrence

risk among asymptomatic family members and descendants. Nevertheless, the appropriate implementation of genetic testing requires a well-established genetic counseling system to provide adequate support [153].

CQ3. Is therapeutic phlebotomy effective in the management of PCT?

Grade of recommendation: B.

Level of evidence: IV.

Recommendation: Phlebotomy is effective in PCT and is recommended as a therapeutic option.

Explanation: Phlebotomy for PCT was first introduced by Ippen [226, 227] with the aim of reducing total body iron stores and hepatic iron content, and its usefulness as a treatment for PCT has since been established. The typical protocol involves repeated phlebotomy of 300–500 mL every 2–3 weeks until hemoglobin levels reach approximately 10–11 g/dL, serum iron 50–60 µg/dL, urinary uroporphyrin 50–100 µg/day, and serum ferritin 15–20 ng/mL. Treatment efficacy is judged by clinical improvement and serial decreases in urinary uroporphyrin levels.

No RCTs have been conducted to evaluate the efficacy of phlebotomy in PCT; however, several case series have examined its usefulness and recurrence. Epstein et al. [228] reported clinical and laboratory improvements in all 20 PCT patients who underwent phlebotomy totaling 2500-8500 mL over 3-8.5 months. During the follow-up of 18 patients, recurrence occurred in 2 cases. Lundvall [229] performed weekly phlebotomy of 400-500 mL in 44 PCT patients until daily urinary uroporphyrin excretion decreased to ≤ 1 mg, and observed the disappearance of skin fragility and ulcerations. In a subsequent follow-up, laboratory recurrence was documented in 9 patients (20%). Singal et al. [230] reported that in 25 PCT patients treated with phlebotomy until serum porphyrin levels declined to 0.9 µg/dL and skin symptoms resolved, recurrence was observed in 7 patients (29%) during the follow-up.

In Japan, no case series studies have been reported, although several case reports exist. Miura et al. [231] reported a 52-year-old male PCT patient treated with 16 sessions of phlebotomy (100–200 mL every 1–2 weeks; total 2160 mL), which normalized urinary porphyrin excretion. Nonaka et al. [232] reported a 55-year-old male PCT patient whose urinary porphyrins markedly decreased following phlebotomy. Shimamoto et al. [233] observed a reduction in urinary uroporphyrin excretion from 1390 µg/day 1 month after phlebotomy initiation in a 57-year-old male PCT patient, although skin symptoms persisted, requiring ongoing treatment. Okayama et al. [234] performed 11 phlebotomies (250–300 mL each) at 4– to 8-week intervals over 1 year (total 3000 mL) on a 53-year-old male patient with PCT, resulting in the resolution of fatigue, anorexia, pigmentation, and blistering; urinary uroporphyrin and coproporphyrin excretion normalized within 6 months and remained within reference ranges thereafter. Fukushima et al. [235] treated a 66-year-old male PCT patient with 6 phlebotomies (400 mL every 2 weeks), leading to an improvement in

diffuse pigmentation, a decrease in serum ferritin from 351 ng/mL to 70.5 ng/mL, and an improvement in liver dysfunction. A meta-analysis by Salameh et al. [183] evaluated recurrence after phlebotomy, analyzing 3 case series comprising 88 patients. Recurrence was observed in 18 patients (20.5%) during follow-up periods of 1–6 years.

The major limitation of plebotomy, frequently noted in reports, is complicated monitoring. Furthermore, in Japan, plebotomy for polycythemia vera, secondary polycythemia, or chronic HCV resistant to interferon or hepatoprotective therapy is not covered under the national health insurance system, only so the treatment of PCT with plebotomy is considered off-label.

In summary, phlebotomy is an established and effective therapeutic option for PCT. However, it should be noted that potential triggering factors for PCT include alcohol, estrogens, iron supplementation, and HCV, and the appropriate management of these contributing factors should also be prioritized.

CQ4. Is treatment with cimetidine, cimetidine combined with lactulose, or UDCA effective for hepatic impairment in EPP?

Grade of recommendation: C1.

Level of evidence: V.

Recommendation: Cimetidine, cimetidine combined with lactulose, and UDCA may each be effective and can be considered as therapeutic options for the treatment of EPP.

Explanation: Cimetidine and combined cimetidine/lactulose therapy: Cimetidine, an H₂ receptor antagonist, was initially reported to be effective in patients with AIP at a daily dose of 800 mg, based on its ability to inhibit hepatic ALAS activity [236]. Tamamoto et al. [177] subsequently reported that the administration of cimetidine in EPP patients reduced erythrocyte protoporphyrin levels, and several case reports have since suggested its potential efficacy in EPP. Tu et al. [237] retrospectively reviewed 3 pediatric patients (<18 years) who had been treated with cimetidine for more than 3 years and found improvements in photosensitivity, cutaneous manifestations, erythrocyte protoporphyrin levels, and liver function. Heerfordt et al. [238] evaluated the efficacy and safety of cimetidine in 18 EPP patients who received 800–1600 mg daily from spring or summer until before winter. Three patients discontinued treatment due to adverse events, such as dizziness, but erythrocyte protoporphyrin levels in the remaining 15 patients decreased on average to 20% of baseline after 4 months, and 11 of the 15 patients showed an improvement in photosensitivity. No significant changes in hematologic parameters or liver enzyme levels were observed. Conversely, Yasuda et al. [239] demonstrated in animal studies that cimetidine does not suppress ALAS activity.

Regarding combination therapy with cimetidine and lactulose, only one case report by Fujimori et al. [178] has been published. They described a 21-year-old male EPP patient who had suffered from recurrent abdominal pain and liver dysfunction with associated liver fibrosis since 18 years old. Initial treatment with UDCA and intravenous glucose was insufficient; therefore,

cimetidine was administered in combination with lactulose in order to suppress hepatic ALAS and limit the re-absorption of protoporphyrin, respectively. Subsequently, jaundice, liver dysfunction, and abdominal symptoms improved. Follow-up liver biopsy 1.5 years after initiating cimetidine/lactulose therapy showed the marked attenuation of periportal fibrosis and protoporphyrin deposition. Lactulose is widely used for the treatment of hyperammonemia and is thought to act by suppressing ammonia-producing gut bacteria; however, no further reports on its efficacy in EPP have been published.

UDCA, a secondary bile acid, stimulates bile secretion and protects hepatocytes from bile acid-induced injury. Evidence for its efficacy in EPP-associated liver dysfunction or cirrhosis is limited to case reports. Gross et al. [179] administered UDCA to eight EPP patients and observed improvements in laboratory findings, but little improvement in clinical symptoms, such as fatigue. They suggested that UDCA may be effective only in the initial stages of liver disease with intrahepatic cholestasis in EPP. Choi et al. [240] demonstrated in a griseofulvin-induced EPP mouse model that UDCA may exert hepatocytoprotective and choleretic effects. Conversely, Abitbol et al. [241] reported that UDCA administration combined with heme arginate injections did not improve the protoporphyric conditions in a FECH-deficient EPP mouse model.

From the above findings, although evidence regarding the efficacy of cimetidine, cimetidine plus lactulose, and UDCA for EPP is limited, these treatments may be considered as potential therapeutic options given their minimal risk of serious adverse effects. However, it should be noted that these oral therapies are not covered by the national health insurance system when administered for EPP and therefore represent off-label use.

CQ5. Is photoprotection (use of sunscreens) effective in the prevention of cutaneous porphyrias?

Grade of recommendation: C1.

Level of evidence: IV.

Recommendation: Sunscreens with appropriate wavelength coverage are effective in preventing photosensitivity symptoms in patients with cutaneous porphyrias.

Explanation: In cutaneous porphyrias, particularly EPP, accumulated protoporphyrin has a peak absorption wavelength of 400–410 nm (approximately 405 nm). In the early 1990s, in vitro studies reported that sunscreens combining 20% zinc oxide and tinted iron oxides were effective in providing protection across UVA and the visible light spectrum [242]. Subsequently, in vivo studies in the 2000s demonstrated the protective efficacy of sunscreens containing 4% titanium dioxide and 5% zinc oxide in the same wavelength range. More recently, Teramura et al. conducted a clinical study on 23 Japanese patients with EPP, in which a make-up base containing titanium dioxide and iron oxides was used as a sunscreen, and reported an efficacy rate of 78% [243].

The sun protection factor, commonly used as an indicator of UV protection, reflects protection only against UVB

(280-315/320 nm) and does not account for the photosensitivity observed in EPP. Therefore, a new index, the photosensitivity protection factor (PPF), has been proposed, which extends the measurement range into the visible spectrum up to 600 nm to better predict photoprotective effects in photosensitive patients [244]. In addition, the porphyrin protection factor has been proposed as an index of protection specifically against light at 408 nm, the absorption peak of protoporphyrin [243]. Sunscreens providing PPF coverage across 300-450 nm, particularly around the 408 nm peak, are considered to be effective for the prevention of photosensitivity in EPP patients. However, as current commercial sunscreens generally do not display PPF values on their labeling, it is necessary to evaluate individually which products provide protection extending into the visible light spectrum.

CQ6. Is the oral administration of β-carotene effective for the prevention of photosensitivity in EPP?

Grade of recommendation: C2.

Level of evidence: II.

Recommendation: Treatment with oral β-carotene for reducing photosensitivity in EPP has been recognized to have some effects; however, in Japan, β-carotene is classified only as a food additive; therefore, its oral use as a therapeutic agent is not recommended.

Explanation: In 1970, Mathews-Roth et al. [175] reported that the oral administration of β-carotene, a precursor of vitamin A, reduced photosensitivity in three patients with EPP. Since then, several studies have examined the efficacy of β-carotene in improving photosensitivity symptoms in EPP. The proposed mechanism is that β-carotene is deposited in the skin and reduces the penetration of light. Reported daily doses of β-carotene have widely varied, ranging from 15 to 300 mg/day, with treatment durations from 2 months to more than 4 months. Among studies reporting benefits, the response rates ranged from 36 to 100%.

RCTs with β-carotene are challenging to conduct as skin discoloration to a yellow-orange hue makes the blinding of patients and investigators difficult. In the RCT conducted by Corbett et al. [176], 11 EPP patients received 100 mg/day of β-carotene daily for 4 months, but no marked difference in photosensitivity symptoms was observed between the β-carotene and placebo groups. In contrast, a pooled analysis of 8 uncontrolled studies [245–252] involving 231 EPP patients reported that 85% experienced a reduction in photosensitivity, while 15% had little or no improvement; no patients reported the worsening of symptoms during treatment [253]. Two studies [246, 250] also assessed erythrocyte protoporphyrin levels and found no significant change during β-carotene treatment.

In Japan, β-carotene is designated as a food additive under Article 10 of the Food Sanitation Act. No Tolerable Upper Intake Level (UL) has been established, but commercially available supplements generally contain 1.8–15 mg per tablet, with a recommendation of 1 tablet per day. According to a notice from the Cabinet Office Food Safety Commission of Japan, both the European Food Safety Authority (EFSA) and the U.S. Food

and Nutrition Board have concluded that current human intervention studies are insufficient to establish a definitive UL for isolated β-carotene. In the United Kingdom, the Expert Group on Vitamins and Minerals has proposed a “safe upper level” of 7 mg/day from supplements, while nutrition societies in German-speaking countries (Germany, Austria, and Switzerland) have concluded that a maximum daily intake of up to 10 mg from all sources is safe.

Daily doses of 60–180 mg/day are typically required for the treatment of EPP; however, these amounts do not reach the β-carotene intake levels found in nutritional supplements commercially available in Japan. Therefore, oral β-carotene therapy is not recommended for the prevention of photosensitivity in patients with EPP.

CQ7. Is shielding from light in the surgical field effective during open surgery, such as thoracotomy or laparotomy?

Grade of recommendation: B.

Level of evidence: V.

Recommendation: Since ceiling lights, surgical lamps, and optical medical devices used in operating rooms emit wavelengths within the visible light spectrum, light shielding of the surgical field is essential during open surgery, such as thoracotomy or laparotomy, in patients with photosensitive porphyrias.

Explanation: Light emitted from ceiling lights, surgical lamps, and optical medical devices used during surgery contains wavelengths within the visible light spectrum. Therefore, exposure of the surgical field to light should be minimized as much as possible during open surgery, such as thoracotomy or laparotomy. There have been reports of severe cutaneous phototoxic burns caused by operative light in patients with EPP undergoing liver transplantation [170, 254]. In a retrospective review of 20 EPP patients who underwent surgery, 1 patient who was not protected by optical filters during the procedure developed severe cutaneous burns and multiple intestinal injuries and subsequently died from sepsis after liver transplantation [170, 171]. In Japan, a patient with VP developed erythema and erosions after approximately 3 h of exposure to surgical lamps [255].

Since all porphyrias other than AIP and ADP can present with photosensitivity, shielding is required during thoracotomy and laparotomy for these patients. Specifically, protection against the blue light spectrum (approximately 380–460 nm) should be provided using acrylic optical filters [24, 256]. Wahlin et al. investigated various filters and reported that the 61 011 filter (Reflectiv SA, Créteil, France) provided the best balance between blocking wavelengths below 470 nm and maintaining adequate illumination [257]. In Japan, WB-400R (Yamahira Co. Ltd., Koshigaya, Saitama, Japan) and DF-Y (Koshin Optical Industry, Hadano, Kanagawa, Japan) are equivalent to the 61 011 filter. However, the use of filters alone results in a reddish hue across the entire surgical field, necessitating additional adjustments, such as combining with alternative light sources during surgery.

CQ8. Is reviewing a patient's medication history useful in the management of porphyrias?

Grade of recommendation: B.

Level of evidence: IV.

Recommendation: The careful management of medication history is essential because certain drugs can precipitate acute porphyric attacks, and drug-induced porphyrinuria or pseudo-porphyria may also occur.

Explanation: In acute porphyrias, it is well established that certain drugs can precipitate acute attacks. Wang et al. identified 52 drugs associated with porphyria using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) [258]. These included antiviral agents (e.g., ritonavir), antimicrobials, the antifungal agent voriconazole, the antituberculosis drug rifampicin, antiepileptic drugs, barbiturates, vasoactive agents, oral contraceptives, progestins, and local anesthetics. CYP enzymes stimulate the synthesis of ALAS1 in hepatocytes; therefore, drugs that induce CYP activity can serve as triggers of acute attacks in patients with acute porphyrias [122, 258]. Consequently, such drugs are contraindicated in patients with acute porphyrias, particularly AIP. It should also be noted that some contraindicated drugs are commonly prescribed, including diclofenac sodium, butylscopolamine, nitrazepam, carbamazepine, trimethoprim, furosemide, and lidocaine [259]. Drug safety in porphyria can be verified using dedicated online databases [260].

Drug administration may also cause elevations in urinary porphyrins, a condition referred to as porphyrinuria, which must be distinguished from inherited porphyrias caused by enzymatic defects in the heme biosynthetic pathway. In drug-induced porphyrinuria, the porphyrin most commonly detected in urine is coproporphyrin. This occurs because certain drugs inhibit the organic anion transporters responsible for excreting coproporphyrins into bile, thereby increasing urinary porphyrin excretion. Examples of such drugs include artesunate, balsalazide, benazepril, chlorpropamide, cortisol, demethylchortletracycline, diflunisal, flavonoids, irbesartan, mefenamic acid, nitazoxanide, penciclovir, probene-cid, stirpentol, telmisartan, and valsartan [164, 165].

In addition, pseudoporphyria presents with photosensitivity similar to PCT but without detectable porphyrins in blood, urine, or feces (Table 8) [261]. Pseudoporphyria is frequently drug-induced, and reported causative agents include naproxen, tetracyclines, fluoroquinolones, voriconazole, furosemide, chlorthalidone, hydrochlorothiazide-triamterene, amiodarone, and cyclosporine [262].

CQ9. Is iron supplementation effective for anemia in EPP?

Grade of recommendation: C2.

Level of evidence: V.

Recommendation: The management of anemia is necessary in EPP and XLP. Iron supplementation should be considered with caution in EPP as it may potentially worsen symptoms, whereas it is generally considered effective in XLP.

Explanation: In patients with EPP and XLP, mild microcytic hypochromic anemia is observed in 30%–60% of cases [76, 263, 264]. Phenotypically, this anemia resembles iron-deficiency anemia; however, whether it directly results from iron deficiency or reflects chronic inflammation has long been debated without consensus [76, 199, 200, 264–268]. Barman-Aksözen et al. examined blood samples from 67 EPP patients and demonstrated that, compared with controls, EPP patients had significantly lower serum ferritin and hepcidin levels and significantly higher zinc protoporphyrin and soluble transferrin receptor levels [200]. Similarly, Bossi et al. reported significantly lower serum ferritin levels in eight EPP patients than in controls. These findings strongly suggest that microcytic hypochromic anemia in EPP is due to iron deficiency [5, 200].

The mechanism underlying decreased serum iron and ferritin in EPP remains unclear but has been attributed to the reduced intestinal absorption of iron or the intestinal loss of iron [267, 269]. Since FECH activity is decreased in EPP, the compensatory up-regulation of ALAS2, the first and rate-limiting enzyme of the home biosynthetic pathway in erythroid cells, occurs, which further promotes protoporphyrin accumulation [200]. In addition, ALAS2 expression positively correlates with serum iron levels; thus, iron supplementation may exacerbate protoporphyrin accumulation by further up-regulating ALAS2 expression. Indeed, several reports have documented the worsening of EPP symptoms following iron supplementation [264, 270, 271]. Consequently, iron deficiency in EPP is considered protective against protoporphyrin accumulation and photosensitivity symptoms [200]. Therefore, iron supplementation for iron-deficiency anemia in EPP should be carefully individualized.

Nonetheless, in EPP patients with severe anemia that interferes with daily activities or with hemoglobin levels below 10g/dL and serum ferritin below 10µg/L, low-dose iron supplementation may be considered, provided serum ferritin does not exceed 100µg/L [76, 200, 264–268]. When administering iron, the potential risk of exacerbating photosensitivity must be weighed against the benefits of improving anemia, and treatment should be conducted under the supervision of a hematologist. Given the risk of iron-deficiency anemia, the periodic monitoring of hemoglobin and iron-related parameters is advisable, approximately once per year [76, 263, 264].

In contrast, in patients with XLP, FECH activity is normal, and iron supplementation reduces erythrocyte protoporphyrin levels and may improve photosensitivity; thus, iron supplementation is considered beneficial in this setting [49, 199, 264, 272].

CQ10. Is active vitamin D supplementation effective for vitamin D deficiency and osteoporosis in patients with EPP?

Grade of recommendation: C1.

Level of evidence: IV.

Recommendation: Since most types of porphyrias are associated with photosensitivity requiring strict photoprotection, vitamin D deficiency and osteoporosis frequently develop. Therefore, an appropriate follow-up should be conducted, and in

patients with confirmed vitamin D deficiency, supplementation with active vitamin D may be considered.

Explanation: In EPP, the primary cutaneous manifestation is painful photosensitivity that occurs within minutes of sun exposure; therefore, strict photoprotection is required for affected patients. Vitamin D is an essential hormone for calcium homeostasis and antitumor activity, and 80%–100% of it is synthesized in the presence of sunlight. Several studies have investigated whether photoprotection in EPP leads to vitamin D deficiency [172, 273–277]. Cross-sectional studies on Dutch and German patients with EPP reported vitamin D deficiency in 29%–72% of patients [172, 273–276]. Notably, men had significantly lower serum 25-hydroxyvitamin D [25(OH)D] levels than women (mean 55 nmol/L vs. 75 nmol/L, respectively) [172]. A negative correlation was also observed between erythrocyte protoporphyrin levels and serum 25(OH)D [172]. In a prospective study on 201 British EPP patients, 63% had vitamin D deficiency. Patients in that study who underwent “hardening” with UVB phototherapy showed a lower prevalence of deficiency (29%), and vitamin D deficiency was more pronounced in winter than in summer. Erythrocyte protoporphyrin levels inversely correlated with serum 25(OH)D, and a shorter latency to the onset of photosensitivity symptoms after sun exposure also inversely correlated with serum 25(OH)D [277]. In a cohort study on 230 Dutch and German patients with EPP, those who received vitamin D supplementation had significantly higher serum 25(OH)D₃ levels than those who did not, whereas the administration of α-melanocyte-stimulating hormone did not affect serum 25(OH)D₃ concentrations [273]. Biewenga et al. further reported osteoporosis in 23% of 44 Dutch EPP patients, significantly higher than the 1% prevalence in controls [274].

These findings indicate that vitamin D deficiency and osteoporosis are common complications of EPP, and the annual monitoring of serum 25(OH)D and bone mineral density is recommended, with corrections using active vitamin D₃ analogs or dietary measures as appropriate. The European guidelines for EPP and XLP also recommend measuring serum 25(OH)D at least once per year [5]. Although no large-scale studies have assessed vitamin D deficiency in other types of porphyrias, strict photoprotection is required in all porphyrias except AIP and ADP; therefore, an appropriate follow-up for vitamin D deficiency is also considered necessary in these patients.

CQ11. Is the erythrocyte protoporphyrin level associated with hepatic impairment in EPP?

Grade of recommendation: B.

Level of evidence: V.

Recommendation: Although evidence regarding the association between erythrocyte protoporphyrin levels and hepatic impairment in EPP is limited, the regular measurement of erythrocyte protoporphyrin levels is recommended as a tool for monitoring hepatic function in EPP.

Explanation: The most serious risk associated with EPP is hepatopathy. Approximately 10%–20% of patients develop cholelithiasis, 20% present with mild hepatic impairment accompanied by

elevations in hepatobiliary enzymes, and about 5% of those with hepatic impairment progress to acute liver failure or cirrhosis [278]. In Japan, Kondo et al. [279] analyzed 154 EPP cases and reported hepatic dysfunction in 35 patients (22.7%) and cirrhosis in 6 patients (3.9%).

In a nationwide epidemiological survey conducted in 2009 by the Research Committee on Epidemiology, Diagnosis, and Treatment of Hereditary Porphyrias [280], 16 of 57 EPP patients (28.1%) exhibited hepatic dysfunction, such as elevated serum bilirubin or transaminases. Furthermore, an analysis of the relationship with erythrocyte protoporphyrin levels revealed that among 42 patients with erythrocyte protoporphyrin levels ≥ 1000 µg/dL, 15 (35.7%) had hepatic impairment, whereas only 1 of 15 patients (6.7%) with levels <1000 µg/dL showed hepatic dysfunction. These findings suggest that maintaining erythrocyte protoporphyrin levels below 1000 µg/dL may be desirable. Similarly, Mizawa et al. [34] reviewed 127 Japanese EPP cases and reported that patients with hepatic dysfunction had significantly higher erythrocyte protoporphyrin levels than those without hepatic involvement.

Reports from Western countries evaluating the association between erythrocyte protoporphyrin levels and hepatic impairment are limited. Bloomer [33] stated that patients with persistently elevated erythrocyte protoporphyrin levels above 1500µg/dL should undergo liver biopsy for an evaluation. Balwani et al. [121] demonstrated that EPP patients with hepatic dysfunction had significantly higher median erythrocyte protoporphyrin levels than those with normal hepatic function (2016µg/dL vs. 1510µg/dL) and concluded that patients with levels exceeding 2000µg/dL required the more intensive monitoring of liver disease. Anstey and Hift [24] also noted that in EPP patients with mild hepatic impairment, the measurement of erythrocyte protoporphyrin should be performed in addition to liver enzyme testing.

In summary, although available data on the association between erythrocyte protoporphyrin levels and hepatic impairment in EPP are not yet sufficient, expert consensus supports the measurement of erythrocyte protoporphyrin as a useful tool for monitoring liver disease in EPP patients. Furthermore, reducing erythrocyte protoporphyrin levels through appropriate therapeutic interventions is considered important for preventing both the onset and rapid progression of hepatic complications.

CQ12. Should intravenous hemin be administered promptly during acute attacks of acute porphyrias?

Grade of recommendation: B.

Level of evidence: III.

Recommendation: In patients with a confirmed diagnosis of acute porphyria who develop an acute attack, the prompt administration of intravenous hemin is recommended.

Explanation: Acute attacks of acute porphyrias occur when relative heme deficiency in the body leads to the up-regulation of ALAS1, resulting in excessive production and the accumulation of the porphyrin precursors ALA and PBG, which exert

neurotoxic effects [15]. Exogenous heme supplementation rapidly suppresses hepatic ALAS1 expression, thereby reducing the production of these toxic precursors [281]. Consequently, the timely initiation of hemin therapy leads to the normalization of ALA and PBG levels, improvements in clinical symptoms, and a reduction in the long-term risk of neurological complications.

In the absence of treatment, or if treatment is delayed during an acute attack, the persistent accumulation of precursors increases the risk of more severe symptoms and irreversible neurological damage. This may result in paralysis of the extremities, respiratory failure, or even life-threatening conditions [282]. Therefore, the most effective strategy to rapidly halt the progression of an attack is the prompt administration of hemin preparations at the time of diagnosis. The early initiation of hemin therapy can prevent further neuronal injury and improve the overall prognosis [283].

Hemin therapy quickly corrects the overproduction and accumulation of ALA and PBG; however, symptomatic relief is dependent on the reduction of these precursors. The efficacy of early hemin administration has been demonstrated in numerous small RCTs and observational studies [283–291]. Furthermore, several international guidelines strongly recommend early hemin therapy for acute attacks of acute porphyrias. For example, both the International Porphyria Network [292] and the U.S. National Organization for Rare Diseases Database guidelines [293] designate intravenous hemin as the standard of care for acute attacks, explicitly noting that early administration provides the most effective relief and prevents complications.

In summary, the rationale for recommending the prompt administration of hemin during acute attacks of acute porphyrias is supported by (i) the underlying pathophysiological mechanism, (ii) the prevention of complications, (iii) the importance of early treatment, and (iv) the endorsement by international guidelines. In Japan, the currently approved therapeutic agent is heme arginate (Normosang), which is typically administered intravenously at 3 mg/kg once daily for 4 consecutive days.

CQ13. Should givosiran be administered to patients with acute porphyria?

Grades of recommendation: A.

Level of evidence: II.

Recommendation: Givosiran is strongly recommended for patients with acute porphyria who experience recurrent attacks.

Explanation: Givosiran is an RNAi therapeutic agent that suppresses the expression of ALAS1, the rate-limiting enzyme in acute porphyrias. By down-regulating ALAS1, givosiran reduces the accumulation of the toxic porphyrin precursors PBG and ALA, thereby preventing acute attacks of acute porphyria [294]. The phase 3 randomized, double-blind ENVISION trial enrolled patients with acute porphyria who had experienced at least two porphyria attacks in the year prior to enrollment. Givosiran treatment reduced the annualized rate of composite porphyria attacks (annualized attack rate) by 74% compared with placebo. In addition, urinary PBG and ALA levels were

significantly reduced by 91% and 86%, respectively, from baseline in the givosiran group [214]. Following the 6-month double-blind period, all patients received givosiran in a 30-month open-label extension, during which patients who switched from placebo demonstrated a 92% reduction in the annualized attack rate, further confirming the suppressive effect on acute exacerbations [215].

Although long-term efficacy has not been fully established, in an extension of a phase 1/2 study in which 16 patients with AIP received givosiran for more than 48 months, the number of acute attacks decreased by 97%, hemin use by 96%, and urinary ALA and PBG levels by 95% and 98%, respectively, from baseline. Significant improvements in QOL were also reported. The most common adverse events were abdominal pain, pharyngeal pain, and injection-site reactions, but no serious adverse events were observed [295]. Real-world studies following trial completion have confirmed similar efficacy and safety. In a study on 11 AIP patients, urinary PBG decreased in all patients, while ALA decreased in 9 patients (82%). Overall, PBG and ALA levels decreased by 75.0% and 71.6%, respectively, from baseline, with significant improvements in QOL; no adverse events were reported [296]. Another study involving 28 AIP patients treated with givosiran for a mean duration of 30 months demonstrated the normalization of ALA in all patients and PBG in 60% of patients. Chronic and acute symptoms both improved in 75% of patients, and the mean number of acute attacks significantly decreased from 2.9 to 0.4 per year. Nine patients experienced recurrent attacks, and three required hemin therapy. QOL scores improved overall. The most frequent adverse event was fatigue, leading to discontinuation in two patients. Mild hepatic and renal dysfunction were also observed, but no life-threatening adverse events occurred [297].

Regarding safety, increases in plasma homocysteine [216], as well as hepatic and renal dysfunctions, have been reported [213, 216]. Therefore, although givosiran is effective for reducing attacks and improving patient outcomes, further studies are needed to evaluate its long-term safety profile.

13 | Conclusion

Porphyrias are metabolic disorders caused by enzymatic abnormalities in the heme biosynthetic pathway. Clinically, cutaneous porphyrias are characterized by recurrent photosensitivity reactions, with each being triggered by sun exposure, whereas acute porphyrias typically present with paroxysmal neuropsychiatric and gastrointestinal symptoms. The diagnosis begins with initial screening through the measurement of porphyrin precursors in blood and urine, while a definitive subtype diagnosis relies on genetic testing.

Although the management of porphyrias remains largely symptomatic, an accurate diagnosis and adequate photoprotection are crucial for improving the prognosis. For instance, in CEP, strict photoprotection can prevent irreversible cutaneous damage, such as digital loss and contractures, whereas in EPP and XLP, photoprotection may help prevent not only photosensitivity symptoms but also hepatic impairment. Acute attacks in acute porphyrias can be life-threatening and, if untreated, may result

in permanent neurological damage or progressive liver failure. Therefore, prompt recognition and an early diagnosis are essential across all types of porphyrias.

We hope that these clinical practice guidelines for the management of porphyrias will serve as a useful reference to support evidence-based diagnoses and treatment in daily clinical practice.

Acknowledgments

This guideline was developed with the support of the Japanese Dermatological Association.

Funding

This work was supported by the Japanese Dermatological Association.

Disclosure

Disclaimer: This guideline was prepared based on the best data available at the time of drafting and represents a collective summary of the opinions of the Guideline Development Committee. Future research findings may necessitate revisions to the conclusions or recommendations presented herein. In addition, under certain clinical circumstances or for specific patients, deviations from these guidelines may be appropriate. Therefore, adherence to these guidelines alone does not absolve physicians of liability for malpractice, nor should deviations from these guidelines necessarily be regarded as negligence.

Conflicts of Interest

All expenses related to the development of these guidelines were fully funded by the Japanese Dermatological Association, with no financial support being received from any organizations, companies, or pharmaceutical industries. The guideline committee members did not receive any honoraria for manuscript preparation, participation in meetings, or related activities. When a committee member was involved in the development of a specific therapeutic drug, that member did not participate in the determination of the recommendation grade for the relevant treatment. Committee members were also required to disclose whether they or their first-degree relatives had received any remuneration from companies involved in the diagnosis or treatment of porphyrias during the period from January 1, 2022 to December 31, 2024. Potential conflicts of interest included honoraria for executive or advisory roles, profits from stocks or shares, royalties from patents, lecture or speaking fees, manuscript fees, clinical research funding (contract research, collaborative research, or clinical trials), educational grants (scholarship donations), endowed chairs or courses funded by industry, and travel expenses, gifts, or other benefits. Details of these disclosures are available at: https://www.derma tol.or.jp/modules/guideline/index.php?contentid=25. S.M. is an editorial board member of The Journal of Dermatology. To minimize bias, S.M. was excluded from all editorial decision-making related to the acceptance of this article for publication.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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