Medical Care
Iron depletion can treat several of the cutaneous porphyrias. High plasma iron levels inactivate uroporphyrinogen decarboxylase, the enzyme deficient in porphyria cutanea tarda (PCT), and induce 5-aminolevulinate, a major regulatory enzyme in the heme biosynthetic pathway. Thus, the activity of the deficient enzyme is reduced further, and porphyrins that cannot be metabolized are produced in increased quantities. Iron depletion also induces the synthesis of porphyrin pathway enzymes. In addition, iron overload resulting from chronic renal failure, a condition not uncommonly seen in association with PCT, is improved by this therapy.
Phlebotomy and apheresis can remove excessive iron in patients with PCT. [10] Standard phlebotomy for adults consists of removal of 250-500 mL of blood once or twice per week. The patient's tolerance and clinical response regulate the exact amount. In patients with chronic renal failure, more frequent small-volume phlebotomies and high-dose erythropoietin combined with phlebotomy are effective.
Monthly neocyte RBC exchange transfusions are reportedly useful in PCT, variegate porphyria (VP), and erythropoietic protoporphyria (EPP).
Erythropoietin is reportedly effective in PCT. By stimulating erythrogenesis, excess iron stored is mobilized and a drop in serum iron, ferritin, and plasma porphyrins is observed. Combining higher doses of erythropoietin with phlebotomy is effective in patients with renal failure. [37]
Deferoxamine forms a stable complex with iron, thereby preventing it from entering into further chemical reactions in PCT and congenital erythropoietic porphyria (CEP). [38] Long-term therapy slows hepatic iron accumulation and retards progression of hepatic fibrosis. Iron is chelated from ferritin and hemosiderin but not from transferrin, cytochromes, or hemoglobin. The chelate readily passes through the kidney, giving the urine a characteristic reddish color. Egan et al reported improvement in CEP in a woman treated with the iron chelator deferasirox to maintain iron deficiency. [39]
Iron oxidizes vitamin C, causing patients with iron overload to become deficient in vitamin C. Vitamin C supplements also increase the availability of iron.
A placebo-controlled study by Ferrer et al suggested that in women with VP, supplementation with both vitamin C and E restores protoporphyrinogen oxidase activity in lymphocytes. [40]
Toxic metabolites have deleterious effects. Porphyrin levels can be reduced by direct methods or with medications that bind porphyrins. These methods are useful adjuncts to iron load reduction therapy or when such therapy is ineffective or limited because of comorbid conditions, such as severe renal disease.
Therapeutic erythrocytapheresis has been combined with plasma exchange to reduce uroporphyrin blood levels. The procedure is continued until urine uroporphyrins are less than 600 mcg/d. [41]
Chloroquine and hydroxychloroquine, two antimalarial medications that belong to the 4-aminoquinolines, chelate and remove hepatic-bound porphyrins by forming water-soluble complexes that are eliminated in the urine. A study by Singal et al demonstrated that for PCT, the safety and efficacy of low-dose hydroxychloroquine (100 mg twice weekly) matches those of phlebotomy. [42] However, a report by Salameh indicated that relapses are more common after 4-aminoquinoline treatment as compared with phlebotomy for PCT. [43]
Cholestyramine is a polymeric resin that binds bile acids to form a nonabsorbable complex, which is excreted unchanged in the feces. This compound also binds carboxylated porphyrins excreted in the bile. By preventing enterohepatic circulation, porphyrins do not reenter the systemic circulation. It has been proposed that sorbent colestipol, operating via the same mechanism, reduces photosensitivity in EPP. [44]
Oral photoprotection can be achieved with free radical scavengers, thereby reducing free radicals, singlet oxygen formation, and the photosensitizing effect of porphyrins.
Beta-carotene is a pigment found in various green and yellow fruits and vegetables and can decrease the severity of photosensitivity reactions in patients with porphyria. Beta-carotene does not alter stool concentrations of protoporphyrins, and plasma or erythrocyte concentrations are not affected. Laboratory evidence suggests that beta-carotene quenches free radicals and singlet oxygen, which are produced when porphyrins are exposed to light and air. Carotenodermia (yellowing of the skin) usually develops after 4-6 weeks and coincides with the start of photoprotection. Protection decreases within 1-2 weeks after discontinuation of therapy. Plasma concentrations of 4-6 mcg/mL are therapeutic for most patients.
Cysteine was found to reduce photosensitivity in patients with protoporphyria. [45] Cysteine is believed to inactivate free radicals. Cysteine is a precursor to glutathione, a free radical scavenger.
N -acetylcysteine has been used, but the efficacy is questionable. Studies have used N -acetylcysteine in PCT elicited by HIV, HCV, and hemodialysis with some benefit. [46]
A small open-label trial by Petersen et al found zinc sulfate to decrease EPP-related photosensitivity. [47] In two multicenter, randomized, double-blind, placebo-controlled trials, afamelanotide, an α-melanocyte–stimulating hormone analog, was shown to decrease pain and improve quality of life in patients with EPP. [48]
Sunscreen protection agents should be used if sun exposure is expected. Sun E45 lotion sun protection factor (SPF) 15 and Sun E45 cream SPF 25 have superior ultraviolet (UV)-A and blue light protection than Report on Carcinogens (RoC) 15+A+B, although all have good UV-B protection for photosensitive patients with EPP. In general, sun-blocking creams containing titanium dioxide or zinc oxide are useful. Sunless tanning agents that impart a pigment to the stratum corneum, especially those containing dihydroxyacetone, can also help.
Acute scleritis in PCT is treated with indomethacin or systemic steroids when standard treatment does not improve the condition. [49]
There have been case reports that radiation therapy can result in significant cutaneous and soft tissue morbidity in PCT, and this should be considered while discussing risks of this therapy. [50]
Newborns with jaundice, hemolysis, and hepatosplenomegaly precipitated by a rare type of undiagnosed porphyria (Harder porphyria) will develop a severe skin reaction if treated with phototherapy for their jaundice. [51, 52]
Surgical Care
Many anesthetics can exacerbate porphyria, requiring an experienced anesthesiologist for proper treatment during surgery.
Cholecystectomy may be required for severe cholelithiasis in CEP. Splenectomy may be required if severe hemolytic anemia develops in CEP.
CEP has been cured with allogenic bone marrow transplant. Risks of this procedure must be carefully considered.
Liver transplant alone is not curative for EPP but instead needs to be combined with bone marrow transplant. [11]
Consultations
Contact a porphyria expert to assist in diagnosis and management of short-term and long-term treatments. Because porphyria spans many disciplines, experts may be certified in the area of metabolic disease, gastroenterology, or hematology. [53]
A hematologist may be particularly helpful if phlebotomy, apheresis, or exchange transfusion procedures are being used. In addition, management of deferoxamine and erythropoietin therapy may also require such an expert. A hematologist should be consulted if bone marrow transplant or splenectomy is considered for CEP.
Seek dermatologist consultation for management of cutaneous lesions.
Seek ophthalmologist consultation if ocular manifestations arise.
Gynecologist consultation may be necessary for menses control because estrogens should be avoided.
Anesthesiology consultation is necessary before sedation in minor procedures or surgery.
Diet
A high-carbohydrate diet can reduce disease severity. A low-carbohydrate diet is strictly forbidden.
Activity
Contact with direct sunlight should be minimized. Sunscreen protection should be used when skin is exposed to the sun.
Shading of glass windows in cars can minimize light exposure during driving.
Activities that could damage skin lesions should be avoided.
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The heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and is then resumed in the mitochondria for the final steps. This figure outlines the enzymes and intermediates involved in the porphyrias. Enzymes names are presented in the boxes. Names of the intermediates are outside the boxes, between arrows. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce one product.
Tables
Type of Porphyria |
Age of Onset |
Incidence per 100,000 Population |
Male-to-Female Ratio |
CEP |
Infancy to early childhood; rare in adults |
300 cases total |
1:1 |
PCT |
Type I: Adulthood Type II (heterozygous mutations): Adulthood Type III (homozygous mutations): Childhood |
United States: 4 United Kingdom: 0.05 |
1:1 |
HCP |
Predominantly adulthood Youngest report was child aged 4 y |
Japan: 1.5 Czech: 1.5 Israel: 0.7 Denmark: 0.05 |
1:20 1:4 2:1 1:1 |
VP |
Heterozygous mutation: After puberty Homozygous mutation: Childhood (rare) |
South Africa: 34 |
1:1 |
EPP |
Infancy to childhood |
0.02 |
1:1 |
Porphyria |
Deficient Enzyme |
Location |
Inheritance |
Chromosome Band |
CEP |
Uroporphyrinogen III synthase |
Cytosol |
Autosomal recessive (AR) |
10q25.3-26.3 |
PCT |
Uroporphyrinogen decarboxylase |
Cytosol |
Autosomal dominant (AD) |
1p34 |
HEP |
Uroporphyrinogen decarboxylase |
Cytosol |
AR |
1p34 |
HCP |
Coproporphyrinogen oxidase |
Mitochondrial |
AD |
3q12 |
VP |
Protoporphyrinogen oxidase |
Mitochondrial |
AD |
1q22-23 |
EPP |
Ferrochelatase |
Mitochondrial |
AD, AR |
18q22 |
Porphyrin Type |
CEP |
PCT |
HCP |
VP |
EPP |
Uroporphyrin |
Significantly increased |
Increased |
Within reference range |
Within reference range |
Within reference range |
Coproporphyrin |
Significantly increased |
Increased |
Significantly increased |
Increased |
Within reference range |
Protoporphyrin |
Within reference range |
Within reference range |
Increased |
Significantly increased |
Significantly increased |
Porphyrin type |
CEP and PCT |
HCP and VP |
5-Aminolevulinate |
Within reference range |
Significantly increased |
PBG |
Within reference range |
Significantly increased |
Uroporphyrin |
Significantly increased |
Increased |
Coproporphyrin |
Increased |
Significantly increased |
