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CHAPTER 58 in acute porphyrias, and the great majority of individuals who inherit deficien-

THE PORPHYRIAS cies of these enzymes remain latent through all or most of their lives. Attacks
are produced by factors that increase hepatic heme synthesis, including certain
drugs, sex steroid hormones and their metabolites and restriction of dietary
calories and carbohydrate. Treatment of acute porphyrias includes glucose
John D. Phillips and Karl E. Anderson loading and hemin infusions, which repress δ-aminolevulinic acid synthase-1,
the rate-limiting enzyme of the heme biosynthetic pathway in the liver.
Cutaneous porphyrias are associated with either blistering skin lesions or,
SUMMARY in erythropoietic protoporphyria (EPP), with acute nonblistering photosensi-
tivity. Blistering skin manifestations are identical in PCT, HCP, and VP. Similar
Porphyrias are diseases that result from derangements of specific enzymes in lesions in congenital erythropoietic porphyria (CEP) are much more severe and
the heme biosynthetic pathway that lead to overproduction and accumulation often associated with loss of digits and facial mutilation. CEP results from a
of pathway intermediates and cause neurologic symptoms, photocutaneous severe deficiency of the fourth enzyme in the pathway and is inherited in an
symptoms or both. Multiple inherited mutations have been identified in all autosomal recessive fashion. Hemolytic anemia is common, and severe cases
the porphyrias. However, porphyria cutanea tarda (PCT), which is caused pri- may be transfusion dependent, and may even present in utero with fetal
marily by an acquired deficiency of the fifth enzyme in the heme biosynthetic hydrops. Hematopoietic stem cell transplantation in early childhood is the
pathway, specifically in the liver, is usually not associated with a mutation of most effective treatment.
this enzyme. EPP is the third most common porphyria and the most common in
Porphyrias can be classified as either hepatic or erythropoietic, depending children. It is usually caused by a deficiency of the final enzyme in the pathway.
on the principal site of initial accumulation of excess pathway intermediates. In most families, inheritance of EPP is best described as autosomal recessive,
Erythropoietic porphyrias are characterized by childhood onset and a generally with a severe ferrochelatase mutation inherited from one parent and a low-
stable clinical course. Hepatic porphyrias almost always develop during adult expression variant allele from the other. X-linked protoporphyria (XLP) has
life, and are more variable because of multiple influences of drugs, hormones, the same phenotype as EPP, but is caused by gain-of-function mutations of δ-
and nutritional factors on the heme biosynthetic pathway in the liver. aminolevulinic acid synthase-2, which is expressed only in erythroblasts and
Porphyrias are also classified as acute or cutaneous. The four acute porphy- reticulocytes. Protoporphyrin-containing gallstones may develop in EPP and
rias are associated with neurologic manifestations that usually occur as acute XLP. An uncommon but potentially life-threatening complication is protopor-
attacks. δ-Aminolevulinate dehydratase porphyria (ADP) is an autosomal phyric hepatopathy, which is a result of the cholestatic effects of protoporphy-
recessive disorder caused by a deficiency of the second enzyme in the pathway rin, and may require liver transplantation. Sequential marrow transplantation
and is the rarest type of porphyria. ADP has been classified as hepatic, but also can prevent recurrent hepatopathy in the transplanted liver.
has erythropoietic features. The three other acute porphyrias, namely acute PCT is an iron-related hepatic porphyria that usually begins in middle or
intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate late adult life. Activity of hepatic uroporphyrinogen decarboxylase (UROD) is
porphyria (VP), are autosomal dominant hepatic porphyrias, and result from reduced in the presence of iron to approximately 20 percent of normal in PCT
deficiencies of the third, sixth, and seventh enzymes in the pathway, respec- by a uroporphomethene inhibitor probably derived from uroporphyrinogen.
tively. HCP and VP are also classified as cutaneous, because photocutaneous Multiple susceptibility factors, including use of alcohol, smoking, estrogens,
lesions may develop, especially in VP. AIP is the most common acute porphyria hepatitis C and HIV contribute. HFE (hemochromatosis gene) mutations that
and the second most common porphyria. Disease expression is highly variable cause excess iron absorption are common in PCT. A minority of patients are
heterozygous for UROD mutations and are said to have familial PCT. Polyhalo-
genated aromatic hydrocarbons cause PCT in laboratory animals and occa-
sionally in humans. PCT responds well to treatment by repeated phlebotomy,
which reduces hepatic iron, or low-dose hydroxychloroquine or chloroquine,
Acronyms and Abbreviations: ADP, δ-aminolevulinate dehydratase deficiency which mobilizes accumulated hepatic porphyrins. Hepatoerythropoietic por-
porphyria; AIP, acute intermittent porphyria; ALA, δ-aminolevulinic acid; ALAD, phyria is the homozygous form of familial PCT, and is usually a severe disorder
δ-aminolevulinic acid dehydratase; ALAS, δ-aminolevulinic acid synthase; ALAS1, that starts in childhood and resembles CEP clinically.
δ-aminolevulinic acid synthase, housekeeping form; ALAS2, δ-aminolevulinic acid
synthase, erythroid-specific form; cDNA, complementary DNA to mRNA template;
CEP, congenital erythropoietic porphyria; CPO, coproporphyrinogen oxidase; CPRE,
coproporphyrinogen oxidase gene promoter regulatory element; CRIM, cross- DEFINITION AND HISTORY
reactive immunologic material; CYP, cytochrome P450; EC, enzyme commission;
EPP, erythropoietic protoporphyria; FECH, ferrochelatase; HCP, hereditary copropor- The porphyrias are a group of metabolic diseases resulting from derange-
phyria; HEP, hepatoerythropoietic porphyria; HFE, hemochromatosis gene; HMB, ments, usually of a genetic nature, in the activity of specific enzymes in
hydroxymethylbilane; IRE, iron-responsive element; IRPs, iron-responsive element the heme biosynthetic pathway, leading to overproduction and accu-
binding proteins; NRF-1, nuclear regulatory factor 1; PBG, porphobilinogen; PBGD, mulation of pathway intermediates. Symptoms of these diseases can be
porphobilinogen deaminase; PCT, porphyria cutanea tarda; PGC-1α, peroxisomal neurologic, photocutaneous, or both. The intermediates that accumu-
proliferator-activated cofactor 1α; PPO, protoporphyrinogen oxidase; PXR, pregnane late include porphyrins and the porphyrin precursors δ-aminolevulinic
X receptor; SCS-βA, β subunit of ATP-specific succinyl coenzyme A synthetase; UROD, acid (ALA) and porphobilinogen (PBG) and their derivatives. Patterns
uroporphyrinogen decarboxylase; UROS, uroporphyrinogen synthase; VP, variegate of these substances in plasma, erythrocytes, urine, and feces are char-
porphyria; XLP, X-linked protoporphyria. acteristic for each porphyria, and are the basis for screening tests and
more comprehensive biochemical characterization.

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