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PORPHYRIAS

These disorders result from altered metabolism in the heme biosynthesis pathway, leading to an accumulation of porphyrins. In the types that affect the skin, the relevant porphyrins are changed to an ‘excited' state after exposure to light. Their energy is then transferred to oxygen to produce reactive oxygen species, which in turn interfere with the membranes of intracellular organelles and so produce cellular damage. Maximal absorption is at 400–410nm (the Soret band), which is at the violet end of the visible light spectrum and is difficult to block well with commercially available sunscreens. A summary of porphyrias that have cutaneous features is provided in Table 17.9. The most important to dermatologists are discussed here.

Erythropoietic protoporphyria

Etiology and pathogenesis

Erythropoietic protoporphyria (EPP) is an autosomal dominant disease that results from an accumulation of protoporphyrin due to a deficiency of ferrochelatase.

Clinical features

Symptoms start in young children. Severe burning pain occurs soon after sun exposure (usually within minutes, but up to within 1h), with subsequent edema and petechial hemorrhages. EPP may also be exacerbated by high-intensity artificial light sources. Significant blisters are uncommon, and diagnosis may be difficult in young children, who scream due to the pain but for whom the relationship to sunlight exposure may not be apparent. Occasionally, the diagnosis may not be made for many years; the oldest patient diagnosed by the author was in her twenties.

Long-term changes may be relatively subtle; they include pitted and linear scarring, and a cobblestoned pattern of skin thickening on hands and face (figs 17.47 and 17.48). Cholelithiasis and eventual hepatic failure may occur in some individuals.

Porphyrin assays should be performed, including erythrocyte fluorescence and plasma porphyrin measurement. Liver function tests are indicated at intervals, and family members should be screened.

Figure 17.47 Erythropoietic protoporphyria. This causes burning pain in early childhood, but later gives rise to small depressed scars at exposed sites. Linear scars, as shown here, are relatively common and possibly represent scratches.

Figure 17.48Erythropoietic protoporphyia. (a) Acute phase: many patients experience burning pain without visible signs, but significant edema or purpura may occur. (b) Longstanding scar-like lesions. Note the predominant involvement of the radial aspect of the hand, which is exposed to more sunlight than the ulnar aspect.

Differential diagnosis

Sunburn may be considered in young children, but the rapidity of developing symptoms after sun exposure is totally dissimilar to sunburn. Solar urticaria has early onset after sun exposure and can be distinguished by the occurrence of whealing, but this may not be apparent from the history. Some rare pediatric photosensitivity disorders may need to be excluded. In patients with skin thickening, various cutaneous infiltrates may need to be considered ( Ch.  11), but this is not usually a feature until well after the diagnosis has been made.

Treatment

This includes sunscreens and sun avoidance. b -Carotene may be beneficial, and antihistamines may reduce symptoms.

Porphyria cutanea tarda

Etiology and pathogenesis

Type I porphyria cutanea tarda (PCT) is sporadic, whereas type II is rare and is an autosomal dominant condition. The major etiologic factor of the sporadic type is alcohol ingestion, although high-dose estrogens (used to treat prostatic cancer) used to be a common trigger before the use of more specific antiandrogens. It can be provoked by estrogens in oral contraceptives, but this is less common as doses are now typically low. Hepatic damage from other causes may also provoke PCT, including hepatitis B. Patients who have HIV infection and hepatitis B often have elevated porphyrin levels but do not necessarily develop clinical PCT.

Clinical features

Porphyria cutanea tarda is typically apparent in middle-aged men who have a history of excessive alcohol intake, but is increasingly common in women. Manifestations include skin fragility, blisters (typically about 1cm in diameter), scarring, and pigmentation (figs 17.49 and 17.50). Milia are common. Hypertrichosis occurs mainly on the cheeks, but the blisters and fragility occur mainly on the dorsum of the hands (presumably due to the greater degree of minor trauma at this site). Sclerodermoid changes and dystrophic calcification are later features.

The evolution is often indolent but more apparent in summer months, and mild cases may be difficult to diagnose, especially in patients who have a manual occupation. Pseudoporphyria (see later) is clinically identical, as is bullous dermatosis of hemodialysis. The differential diagnosis includes dermatitis, scabies, and other photosensitivity disorders. Variegate porphyria should be excluded by porphyrin assay.

Examination of urine with a Wood's lamp may show characteristic pink fluorescence (figs 17.51 and 17.52). This can be accentuated by acidification and extraction of porphyrins into a layer of amyl alcohol. Formal porphyrin assays are important, and characteristically demonstrate elevated urinary uroporphyrin levels. Skin biopsy shows thickened basement membrane at the dermo–epidermal junction, and dermal papillae project into the blister space (a pattern known as festooning). Abnormalities of liver function tests, elevated serum glucose levels, and iron overload are all common.

Figure 17.49Porphyria cutanea tarda. Blisters are typically unilocular, up to about 1 cm in diameter, and have clear fluid content, as shown here.

Figure 17.50Phytophotodermatitis on the leg. The pigmentation is often in a streaky pattern where limbs have brushed against vegetation.

Figure 17.51Porphyria cutanea tarda: urine sample. This has a slightly darker color compared with that of the control urine.

Figure 17.52Porphyria cutanea tarda (PCT): urine sample. Same urine samples as shown in Figure 17.51, demonstrating pink fluorescence of the PCT urine sample under Wood’s light.

Differential diagnosis

Blisters occurring mainly on the dorsum of the hands are rare in any other disorder, but simple burns or trauma may be blamed (especially as there is associated skin fragility), and occasionally drug reactions. A lot of patients with PCT have been treated for presumed ‘eczema' prior to referral. Other forms of porphyria (notably variegate porphyria, discussed later) and the pseudoporphyrias (see later), especially drug-induced forms, are important considerations.

Treatment

Identified triggers such as excessive alcohol intake should be avoided, but improvement is typically slow. Venesection is usually effective, probably by mobilizing and depleting the iron overload: 500mL of blood is removed every week or fortnight until the hemoglobin level falls to about 11 g/dL.

Chloroquine or hydroxychloroquine bind porphyrins, and are then excreted in the urine. Twice-weekly, low-dose administration is safer than higher-dose regimens.

Deferoxamine (desferrioxamine) has also been used to decrease iron levels but is probably not as effective as venesection.

Patients who have porphyria and chronic renal failure and are on dialysis pose a particular problem (fig.17.53). Venesection is contraindicated, as they may already be anemic, and chloroquine–porphyrin complexes do not dialyze out. Erythropoietin can increase heme synthesis and reduce porphyrin levels in some of these patients.

Figure 17.53Porphyria cutanea tarda in a patient having dialysis. This is a difficult management problem.

Variegate porphyria

Variegate porphyria (VP) is most simply viewed as a hybrid of PCT and acute intermittent porphyria (AIP); it has cutaneous features similar to those of PCT, but the same neurologic features that characterize AIP. Additionally, numerous drugs may provoke AIP symptoms, so the patient with VP will need advice on avoidance of these. It is therefore important to differentiate VP from PCT by appropriate blood, urine, and stool samples (especially in younger patients without an obvious PCT trigger such as alcohol, or in those with a personal or family history of unexplained internal symptoms). It is particularly common in South Africa .

Pseudoporphyrias

Etiology and pathogenesis

These disorders fall into three main groups.

Figure 17.54 Pseudoporphyria due to excessive use of a UVA-producing tanning sunbed. Most cases of pseudoporphyria are drug-induced, especially due to non-steroidal antiinflammatory drugs.

Clinical features and differential diagnosis

All features are as for PCT, except for the porphyrin tests, which are negative.

Treatment

This comprises withdrawal of the trigger.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.