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Chapter 38 Heme Biosynthesis and Its Disorders 505

Pseudoporphyria and Renal Dialysis
The term pseudoporphyria has been used to describe a bullous
dermatosis associated with a number of dermatologic conditions that
bear some resemblance to porphyria. 114 This photosensitivity is often
induced by drugs such as the tetracyclines, naproxen, furosemide,
voriconazole, oxaprozin, and many others. In these conditions, there is
no alteration in porphyrin metabolism or excretion. It is therefore incor-
rect to name any of them porphyria; the term pseudoporphyria should
not be applied to them, but only to conditions in which alterations of
porphyrin metabolism can be found, such as the bullous dermatosis
of hemodialysis. 113
Patients with renal failure can present with many biochemical
features of porphyria before hemodialysis. These abnormalities normal-
ize after dialysis, especially when electrolyte abnormalities such as
zinc deficiency are also corrected. 115 In a considerable proportion of
patients with chronic renal failure, skin changes resembling porphyria
cutanea tarda (PCT) develop some months to years after the onset of
maintenance hemodialysis. In a minor proportion, genuine PCT can be
Fig. 38.6 A BULLOUS SKIN LESION OF PORPHYRIA CUTANEA diagnosed. 116 In such cases, there are elevated total porphyrin levels in
TARDA. plasma and in urine if the patient is not anuric. These patients present a
therapeutic dilemma because they are normally anemic and unsuitable
for phlebotomy therapy.
disease, sometimes with cirrhosis. There is an association with hepa-
tocellular carcinoma. Hepatomegaly is particularly common when
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alcohol intake is excessive. channeling of iron from the cytoplasm to the mitochondrial matrix.
Immunologic studies on human protoporphyria show that immuno-
logically reactive ferrochelatase is present, but that enzyme activity in
Precipitating Factors three subjects was on average only 17% of normal. Gain-of-function
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mutations in the ALAS2 gene have recently been described that result
Many patients with PCT have multiple precipitating factors, includ- in increased erythrocyte protoporphyrin despite normal ferrochelatase
ing mutations of the HFE gene, hepatitis C infection, or exposure to activity. This newly described, X-linked dominant erythropoietic
estrogen. 104,105 Excessive alcohol intake is an important precipitating protoporphyria, leads to accumulation of protoporphyrin in amounts
agent, perhaps because of increased hepatic iron deposition in alco- sufficient to cause photosensitivity and hepatic damage. 34
holics. However, certain halogenated hydrocarbons are sometimes
implicated. PCT may also develop in people treated with hemodialy-
sis for kidney failure. An outbreak of cutaneous hepatic porphyria in Genetics
southeast Turkey in 1956 was traced to seed wheat dressed with the
fungicide hexachlorobenzene. A neoplastic subgroup has been identi- EPP inheritance resembles an autosomal dominant disorder with
fied in which PCT is associated with benign or malignant liver incomplete penetrance; however, the disease usually results from
tumors. inheritance of a FECH null allele together with a low-expression
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mutation. Haplotype segregation analysis has shown intronic
nucleotide polymorphisms in the ferrochelatase gene (FECH) that
Differential Diagnosis produces aberrant splicing of mRNA to a form that degrades more
123
rapidly, resulting in enzyme deficiency. Although these disease-
Other causes of bullous or vesicular skin lesions should be excluded, associated polymorphisms are common, 124,125 there is heterogeneity
such as a drug reaction (see box on Pseudoporphyria and Renal of the molecular defect, including aberrant splicing and loss of
Dialysis) or chronic renal failure. The distinction between PCT, function of the mitoferrin protein. 19,117,121,126,127 The erythroid-specific
variegate porphyria, and hereditary coproporphyria rests on bio- ALAS gene resides on the X chromosome, and mutations in exon 11
chemical testing of urine and feces, with the highest levels of urinary have been described in X-linked dominant erythropoietic protopor-
uroporphyrin found during attacks of PCT (see Table 38.3). phyria. Recombinant mutants have been shown to increase enzyme
activity by two- to threefold, which leads to protoporphyrin
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Erythropoietic Protoporphyria overproduction.

Biologic and Molecular Aspects Clinical Features

Although not described until 1961, this form of EPP, also known as The clinical features are mainly cutaneous on exposure to sunlight
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erythrohepatic protoporphyria, is much more common than congeni- and can occur at any age, including infancy and childhood. They
tal EPP. Ferrochelatase activity is reduced in peripheral blood, liver, include pruritic urticarial swelling and redness of the skin on exposure
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bone marrow, and skin, and protoporphyrin is synthesized in excess. to sunlight. The most distressing symptom is an unbearable burning
The erythroid progenitor cells (i.e., burst-forming units-erythroid sensation on the affected parts. Remarkably, such features are ame-
[BFU-E]) in EPP patients show intense fluorescence when viewed liorated during pregnancy, which has been linked to lowered proto-
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under 405-nm light. The gene mutation in EPP shows heterogeneity porphyrin levels. Hepatic involvement, which occurs in later life,
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as in other porphyrias. The last enzyme of the biosynthetic pathway, involves deposition of hepatotoxic protoporphyrin in the liver and
ferrochelatase, is important because its endogenous activity is rela- can lead to fatal liver failure from an active chronic hepatitis with
131
tively low, and it could act as a control point in the pathway. Fer- cirrhosis. Such protoporphyrin deposition may also cause choleli-
rochelatase ligates iron bound to three cysteine residues in an thiasis; the gallstones contain high concentrations of protoporphyrin.
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iron-sulfur cluster, the mutation of which leads to decreased The liver disease of EPP seems to correlate with erythrocyte proto-
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132
enzyme activity. An oligomeric complex of ferrochelatase, ABCB10 porphyrin concentrations. Mild microcytic anemia has been
and mitoferrin in the mitochondrial membrane would allow for reported, 133,134 as well as mitochondrial iron accumulation and ring