Page 589 - Hematology_ Basic Principles and Practice ( PDFDrive )

504 Part V Red Blood Cells

Nonacute or Cutaneous Porphyrias heterozygous mutations. Mutations in the uroporphyrinogen
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decarboxylase are found in around one-third of patients with PCT.
In all cutaneous porphyrias, porphyrins (which are photosensitizing) In inherited and acquired forms, there is diminution in the activity
are deposited in the upper layers of the skin, and they are responsible of hepatic uroporphyrinogen decarboxylase, which converts uropor-
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for the characteristic skin lesions. In the development of these phyrinogen to coproporphyrinogen by the stepwise decarboxylation
lesions, reactive oxygen species and other radicals are formed and of the acetyl groups to methyl groups. The mechanism of enzyme
probably induce oxidative membrane damage, particularly to mast inhibition has recently been elucidated, whereby iron-dependent
cells, which enables complement activation as one part of the oxidation of uroporphyrinogen generates uroporphomethene, a
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inflammatory reaction (see box on Management of Nonacute competitive inhibitor of uroporphyrinogen decarboxylase. Most
Porphyria). carriers of mutant uroporphyrinogen decarboxylase are not clinically
evident unless precipitating factors are present. Iron alone or chlori-
Porphyria Cutanea Tarda or Cutaneous nated hydrocarbons can diminish activity of uroporphyrinogen
Hepatic Porphyria decarboxylase, and this effect is greatly potentiated when both are
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given together.
In a murine model, precipitation of uroporphyria
by chlorinated hydrocarbons is dependent on hepatic cytochrome
Biologic and Molecular Aspects P450 Cyp 1A2 oxidase activity, and inherited variations in enzyme
function may modulate susceptibility to PCT in humans. 101
PCT exists in inherited and acquired/sporadic forms. Type I, or In sporadic (type I) PCT, there is no evident genetic basis for the
sporadic PCT, comprises 70% to 80% of cases and is associated with condition and low uroporphyrinogen decarboxylase activity is
50% level of uroporphyrinogen decarboxylase activity. PCT type II restricted to the liver. Patients may have clinical and biochemical
or familial PCT results from heterozygous mutations in uroporphy- evidence of liver disease. Hepatic siderosis invariably occurs, and iron
rinogen decarboxylase, whereas a more severe form, hepatoerythro- is one of the causative agents in acquired PCT. An association of PCT
poietic porphyria (HEP), results from homozygous or compound with hereditary hemochromatosis has been documented, with about
20% of PCT patients being homozygous for the Cys282Tyr mutation
in the HFE (“High Fe”) gene, a defect that characterizes hereditary
hemochromatosis. 103–105 These results strongly implicate the HFE
Management of Nonacute Porphyria gene as a genetic susceptibility factor in acquired PCT. An association
between PCT and hepatitis C infection is well documented, and in
Patients should avoid exposure to sunlight and use sunblock (to filter
Soret band light) and physical barriers such as cotton gloves. countries with high prevalence rates, hepatitis C virus may be the
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dominant risk factor. An apparent association has emerged between
Porphyria Cutanea Tarda human immunodeficiency virus (HIV) infection and PCT. It is
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The clinical features are reversed by removing any precipitating agent possible that therapy for HIV with zidovudine precipitates the
such as alcohol, halogenated hydrocarbons, and drugs. The patient disease, but it is more likely that the association is merely coincidental
should be screened for hepatic neoplasm and hepatitis C infection. The or that the viral infection unmasks the preexisting uroporphyrinogen
mainstay of treatment is to remove liver iron by venesection of 500 mL decarboxylase defect. 108
of blood weekly until clinical remission occurs or until the hemoglobin
level falls below 12 g/dL. Chloroquine, at low doses of 125 mg twice per
week for several months, has also been helpful because it enhances
urinary clearance of porphyrin. When this is not possible, oral cimeti- Genetics
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dine has been used. When venesection is difficult, parenteral and
orally active iron chelators can be used to reduce liver iron stores. It is Whereas familial PCT is inherited in an autosomal-dominant mode,
of value to screen the patient and first-degree relatives for hereditary HEP is inherited in an autosomal-recessive pattern. As in the other
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hemochromatosis. genetic lesions in the porphyrias, there is heterogeneity in the muta-
Erythropoietic Protoporphyria tions causing PCT and HEP phenotypes. 110,111 In the inherited form,
Oral β-carotene offers effective protection in erythropoietic porphyria more than 120 different mutations (HGMD Professional 2015.1,
(EPP) against solar sensitivity. It does so by quenching the radical for- www.hgmd.org) have been identified in uroporphyrinogen decarbox-
mation that is a feature of the skin damage. Yellowing of the skin (i.e., ylase, many of which lie near the dimer interface, resulting in an
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carotenemia) is one side effect. Afamelanotide, an alpha-melanocyte- unstable protein and reduced enzyme activity. In different popula-
stimulating hormone, is effective for decreasing photosensitivity in tion groups, it is difficult to find the relative numbers of acquired
EPP by increasing melanin production, and has shown efficacy and and familial disease. In one analysis in Hungary, 77.5% of patients
tolerability for the long-term treatment of EPP. 90,91 Interruption of the were found to suffer from the acquired form, and of the patients with
enterohepatic protoporphyrin circulation by bile salt–sequestering the familial disease, females were affected more than males, suggesting
agents such as cholestyramine reduces plasma protoporphyrin levels
and may retard the development of the liver disease. Liver transplanta- that inheritance may predispose patients to estrogen-precipitated
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tion has been reported to be an effective measure in preventing the disease.
progression of this disease. 92,93
Congenital Erythropoietic Porphyria Clinical Features
The severity of hematologic manifestations are predictors of a poor
prognosis, and patients with hemolytic anemia or thrombocytopenia The most striking clinical feature of both forms of PCT is a bullous
should be considered for allogeneic hematopoietic stem cell transplan-
tation (HSCT). The majority of patients treated with allogeneic HSCT dermatosis on light-exposed areas. This starts as erythema and pro-
have achieved long-term symptomatic cures. 94,95 Erythropoiesis should gresses to vesicles that become confluent to form bullae (Fig. 38.6),
be reduced by means of erythrocyte hypertransfusion and by hematin which may hemorrhage and leave scars; pruritus is often troublesome.
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or heme arginate infusion. However, care should be taken when Milia are common and may precede or follow vesicle formation.
prescribing heme arginate, as overdosing may cause acute hepatic Facial hypertrichosis is common and may serve as a diagnostic clue.
failure. Splenectomy and chloroquine therapy (125 mg twice weekly) In less severe cases, increased fragility of the skin may be the only
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have an ameliorating effect, as does hypertransfusion, but life expec- clinical sign. In severe cases, photomutilation can result, usually
tancy is usually severely shortened. Therapeutic potential has been because of infection of slowly healing lesions.
shown with the use of clinically approved proteasome inhibitors, such The thickening and scarring with calcification has been described
as bortezomib, which prevent enzymatically active uroporphyrinogen III
synthase (UROS) mutants from early degradation in a murine model, as pseudoscleroderma. Hyperpigmentation is common, and women
and gene therapy using induced pluripotent stem cells. 97,98 often complain of hirsutism. Neurologic change is not observed.
Patients may have clinical and biochemical evidence of chronic liver