AUTHOR: Relindis Azenwi Fru, MD
Porphyrias are rare inherited (mostly autosomal dominant) disorders due to deficiencies of heme synthesis enzymes. Table E1 classifies the various types. They are named after the Greek word porphurus (“purple”), after the red fluorescence of porphyrins exposed to ultraviolet light.
Table E2 summarizes the various types of porphyrias.
Acute intermittent porphyria (AIP)
Hereditary coproporphyria (HCP)
Congenital erythropoietic porphyria (CEP)
Hepatoerythropoietic porphyria
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Equal female-to-male ratio, except for AIP (female predominance). Pubertal onset is common.
Acute intermittent porphyria is more prevalent in northern Sweden (1:1000); variegate porphyria is more common in descendants of Dutch settlers from South Africa (both due to founder effect).
There are two broad categories of acute porphyrias. These include:
- Acute hepatic porphyrias (Neurovisceral porphyrias): Comprising four subtypes, AIP, VP, HCP, and ALA-D
- Cutaneous porphyrias: There are two main types, sporadic and familial forms. PCT is the most common subtype of porphyria. PCT is associated with hepatitis C. PCT is an acquired inhibition in uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the pathway. A heterozygous disease variant in the UROD gene predisposes up to 20% of individuals (low penetrance).
- Porphyrias can present as skin stigmata (porphyria cutanea), neurologic symptoms (acute intermittent porphyria), or both (variegata). Skin stigmata (Figs. E1, E2,E3) are the result of absorption of solar radiation by porphyrin and consequent blistering skin findings. Porphyrins do not cross the blood-brain barrier and only affect the autonomic and peripheral nervous systems. However, vasospasm can cause CNS findings. Neurologic symptoms in acute attacks include abdominal pain, vomiting, constipation, and urinary retention. Pain in the back or extremities is common. There is no convincing evidence that delta-aminolevulinic acid is the cause of pain in acute porphyrias. Motor neuropathy affects proximal muscles of upper extremities and the sensory component affects the trunk. Seizures associated with severe hyponatremia may occur. Hallucination, insomnia, restlessness, and psychosis are described. Porphyrias can be acute or chronic. Precipitating factors in acute porphyria are summarized in Table E3.
AIP is the most common form of the four neurovisceral porphyrias. It is inherited in an autosomal dominant fashion. The disorder occurs via deficiency of the enzyme porphobilinogen deaminase, which is the third enzyme in the heme biosynthetic pathway. Patients typically present with severe abdominal pain, nausea, vomiting, dark urine, +/–anemia, and otherwise a negative workup. They can also present with urinary retention, neurologic symptoms (sensory, motor, autonomic dysfunction).
Oral contraceptive pills or sex hormones, tobacco abuse, malnutrition, and stress can exacerbate or precipitate symptoms of AIP.
The diagnosis of AIP is confirmed by decreased erythrocyte PBG deaminase activity and/or mutation in the gene encoding PBGD (hydroxymethylbilane synthase).
These disorders are in the differential of acute abdomen; however, characteristically, rebound tenderness is not present.
TABLE E1 Porphyrias: Clinical Involvement, Enzymatic Etiology, and Chromosomal Location
| Porphyria (Synonym) | Acute Attack, Skin and Organ Involvement | Enzyme of Heme Biosynthesis Affected | Chromosome Location |
|---|---|---|---|
| X-linked sideroblastic anemia | Bone marrow | 5-Aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2) | Xp11.21 |
| X-linked dominant protoporphyria | Skin, red cells, liver | 5-Aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2) | Xp11.21 |
| ALA dehydratase deficiency porphyria (plumboporphyria) | Acute liver | ALA dehydratase (porphobilinogen synthase) | 9q33.1 |
| Acute intermittent porphyria (intermittent acute porphyria) | Acute liver | Porphobilinogen deaminase (hydroxymethylbilane synthase) | 11q23.3 |
| Congenital erythropoietic porphyria (Günther disease) | Skin, red cells, bone marrow | Uroporphyrinogen III synthase | 10q25.2-q26.3 |
| Porphyria cutanea tarda (symptomatic porphyria, cutaneous hepatic porphyria) | Skin, liver | Uroporphyrinogen decarboxylase | 1p34 |
| Hereditary coproporphyria | Acute skin, liver | Coproporphyrinogen oxidase | 3q12 |
| Variegate porphyria (porphyria variegata) | Acute skin, liver | Protoporphyrinogen oxidase | 1q22 |
| Erythropoietic protoporphyria (erythrohepatic protoporphyria) | Skin, red cells, liver | Ferrochelatase (heme synthase) | 18q21.3 |
ALA, 5-Aminolevulinate.From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.
- Porphyrin binds to iron to form heme, the core of the hemoglobin molecule. Porphyrins are synthesized in the cytosol and mitochondria, and mutations in any of the eight enzymes involved in heme synthesis can result in porphyrias. When the defect is physiologically significant, it results in overproduction of pathway precursors preceding the defective step that enter the circulation and are excreted into urine or bile.
- This metabolic pathway is limited only by iron in the red blood cell and not by its end product, heme, which therefore is used in the treatment of hepatic porphyrias, where it inhibits the ALAS enzyme. Table E4 summarizes the distribution of porphyrins in red cells, urine, and feces in different forms of porphyria.
TABLE E2 Classification of Porphyrias
| Classification | Disease | Biochemistry | Clinical Features |
|---|---|---|---|
| Acute porphyria | Acute intermittent porphyria | Increased ALA and PBG | Acute attack |
| Variegate porphyria | Increased ALA and PBG; increased porphyrin | Acute attack; photosensitivity | |
| Hereditary coproporphyria | Increased ALA and PBG; increased porphyrin | Acute attack; photosensitivity | |
| ALA dehydratase deficiency porphyria | Increased ALA; increased porphyrin | Acute and chronic neuropathy | |
| Nonacute porphyria | Porphyria cutanea tarda | Increased porphyrin | Photosensitivity |
| Erythropoietic protoporphyria | Increased porphyrin | Photosensitivity | |
| Congenital erythropoietic porphyria | Increased porphyrin | Photosensitivity | |
| X-linked dominant protoporphyria | Increased porphyrin | Photosensitivity | |
| Porphyrinurias | Lead, alcohol, iron deficiency anemia, liver disease | Various biochemical manifestations | Various clinical presentations |
ALA, 5-Aminolevulinate; PBG, porphobilinogen.
From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.
Figure E1 Porphyria cutanea tarda.
Eroded blisters and crusts.
Courtesy the Yale Residents’ Collection. From Skorecki K et al: Brenner & Rector’s the kidney, ed 10, Philadelphia, 2016, Elsevier.
