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Cutaneous
porphyrias tend to manifest as undulating or unremitting disease
with a relatively steady production of phototoxic porphyrins in
the liver or bone marrow. These porphyrins accumulate in the skin
and, on sunlight exposure (visible light, including near-ultraviolet
[UV]), generate cytotoxic radicals that produce cutaneous manifestations.
Cutaneous porphyrias include porphyria cutanea tarda, erythropoietic protoporphyria (EPP), and the extremely rare hepatoerythropoietic porphyria and congenital erythropoietic porphyria (see Table 5: Porphyrias: Some Less Common Porphyrias ). The acute porphyrias variegate porphyria and hereditary coproporphyria also have cutaneous manifestations.
In all cutaneous porphyrias except EPP, cutaneous photosensitivity presents as fragile skin and bullous eruptions. Skin changes generally occur on sun-exposed areas (eg, face, neck, dorsal sides of fingers and hands) or traumatized skin. The cutaneous reaction is insidious, and often patients are unaware of the connection to sun exposure. In contrast, the photosensitivity in EPP occurs within minutes or hours after sun exposure, presenting as a burning pain that persists for hours, often without any objective signs on the skin.
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Table 5
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Some Less Common Porphyrias
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Description
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Symptoms and Signs
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Diagnosis
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Treatment
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Congenital erythropoietic porphyria (Günther disease)
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Deficiency of uroporphyrinogen III cosynthase
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In utero or shortly after birth: Severe cases present as nonimmune hydrops
Soon after birth: Skin blistering, anemia, red urine, dark diapers giving off a red fluorescence under UV light
In adulthood: Facial disfiguration, increased hair growth, corneal scarring (possibly severe), hemolytic anemia, splenomegaly, erythrodontia, deposition of porphyrins in bone, bone demineralization (possibly substantial)
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Porphyrins in plasma, urine, and stool elevated to levels higher than those in other porphyrias
Urinary ALA and PBG virtually normal
Confirmed by low RBC uroporphyrinogen III cosynthase activity
For in utero diagnosis, confirmation of increased amniotic porphyrins
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Avoidance of sunlight (including lights for treating neonatal hyperbilirubinemia)
Use of sun-protective clothing
Avoidance of skin trauma
Prompt treatment of secondary bacterial infections to help prevent scarring
Splenectomy, which may benefit patients with hemolytic anemia
Repeated RBC transfusions to keep bone marrow porphyrin production low
Bone marrow transplantation
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Hepatoerythropoietic porphyria
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Deficiency of uroporphyrinogen decarboxylase
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Skin blistering
Red urine
Anemia
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Elevated isocoproporphyrin in stool and urine
Elevated zinc protoporphyrin in RBCs (to differentiate from PCT)
Confirmed by very low RBC uroporphyrinogen decarboxylase activity
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Phlebotomy, which may benefit patients with milder cases
Treatment of severe disease similar to that of congenital erythropoietic porphyria
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Dual porphyria
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Disorders resulting from deficiencies of > 1 enzyme of the heme biosynthetic pathway
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Clinical and biochemical manifestations of both disorders
In acute porphyrias: Neurovisceral symptoms triggered by porphyrogenic agents
In cutaneous porphyrias: Hypersensitivity to sunlight with blistering and fragile skin
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Porphyrin and porphyrin precursor excretion patterns
Confirmed by family history and enzyme analyses
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In acute porphyrias: avoidance of triggering agents
In cutaneous porphyrias: skin protection and avoidance of sunlight
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ALA =
δ-aminolevulinic acid; PBG = porphobilinogen; PCT = porphyria cutanea tarda; UV = ultraviolet.
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Porphyria
Cutanea Tarda
Porphyria
cutanea tarda (PCT) is a comparatively common porphyria affecting
mainly the skin. Liver disease is common. Symptoms include fragile
skin and blisters affecting sun-exposed areas. Iron plays a key
role in pathogenesis. Several environmental factors lower the threshold
for the phototoxic skin reaction, including alcohol ingestion, estrogens,
hepatitis C infection, and possibly HIV infection. Drugs, with the
exceptions of iron and estrogens, are not triggers. Diagnosis is
by porphyrin analysis of urine and stool. Differentiation from the
acute cutaneous porphyrias HCP and VP is important. Treatment includes
iron depletion by phlebotomy and forced porphyrin excretion by treatment
with chloroquine. Prevention is by avoidance of sunlight, alcohol,
estrogens, and iron-containing drugs.
Pathophysiology
PCT results from hepatic deficiency of uroporphyrinogen decarboxylase (UPGD—see Table 1: Porphyrias: Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency). In about 80% of patients, the responsible mutation is sporadic; the remaining 20% are hereditary.
Porphyrins accumulate in the liver and are transported to the skin, where they cause photosensitivity. The 50% decrease in UPGD activity in heterozygous patients is insufficient to cause clinical PCT. Other factors must further impair enzyme activity. Iron plays a central role, probably by generating oxygen radicals that inhibit UPGD by oxidizing its substrate; thus, hemochromatosis is a significant risk factor. Alcohol, estrogens, and chronic viral infection probably contribute in different ways by increasing iron activity in hepatic tissue. The drugs that commonly trigger acute porphyria (see Table 4: Porphyrias: Drugs and Porphyria*) do not trigger PCT.
Liver disease is common in PCT and may be due partly to porphyrin accumulation, chronic hepatitis C infection, concomitant hemosiderosis, or excess alcohol ingestion. Cirrhosis occurs in ≤ 35% of patients and hepatocellular carcinoma in 7 to 24% (more common in middle-aged men).
The 2 major forms of the disease, types 1 and 2, have the same precipitants, symptoms, and treatment. Overall prevalence may be on the order of 1/10,000.
In type 1 PCT (sporadic), decarboxylase deficiency is restricted to the liver and no genetic background is recognized. It usually manifests in middle age or later.
In type 2 PCT (familial), decarboxylase deficiency is inherited in an autosomal dominant fashion with limited penetrance. Prevalence is lower than in sporadic PCT. Deficiency occurs in all cells, including RBCs. It may develop earlier than type 1, occasionally in childhood.
Secondary PCT-like conditions (pseudoporphyria) may occur with certain photosensitizing drugs (eg, furosemide, tetracyclines, sulfonamides, some NSAIDs). Because porphyrins are poorly dialyzed, some patients receiving long-term hemodialysis develop a skin condition that resembles PCT; this condition is termed pseudoporphyria of end-stage renal disease.
Symptoms and Signs
Patients present with fragile skin, mainly on sun-exposed areas. Phototoxicity is delayed: patients do not always connect sun exposure with symptoms.
Spontaneously or after minor trauma, tense bullae develop. Accompanying erosions and ulcers may develop secondary infection; they heal slowly, leaving atrophic scars. Sun exposure occasionally leads to erythema, edema, or itching. Hyperemic conjunctivitis may develop, but other mucosal sites are not affected. Areas of hypopigmentation or hyperpigmentation may develop, as may facial hypertrichosis and pseudosclerodermoid changes.
Diagnosis
In otherwise healthy patients, fragile skin and blister formation suggest PCT. Differentiation from acute porphyrias with cutaneous symptoms (variegate porphyria [VP] and hereditary coproporphyria [HCP]) is important, because in patients with VP and HCP, the erroneous prescription of porphyrogenic drugs may trigger the severe neurovisceral symptoms of the acute porphyrias. Previous unexplained neurologic symptoms or abdominal pain may suggest an acute porphyria. A history of exposure to chemicals that can cause pseudoporphyria should be sought.
Although all porphyrias that cause skin lesions are accompanied by elevated plasma porphyrins, elevated urinary uroporphyrin and heptacarboxyl porphyrin and fecal isocoproporphyrin indicate PCT. Urine levels of porphyrin precursor porphobilinogen (PBG) and, usually, δ-aminolevulinic acid (ALA) are normal in PCT. RBC activity of UPGD is normal in type 1 PCT but decreased in type 2.
Because concurrent hepatitis C infection is common and may be asymptomatic, serum markers for hepatitis C (see Hepatitis: Serology) should be investigated.
Treatment
Two different therapeutic strategies are available:
These strategies can be combined for more rapid remission. The treatment is monitored by determinations of urinary porphyrin excretion every other or every 3rd month until full remission.
Iron removal by phlebotomy is usually effective. A pint of blood is removed every 2nd or every 3rd week; shorter intervals unnecessarily risk causing anemia. When serum ferritin falls slightly below normal, phlebotomy is stopped. Usually, only 5 to 6 sessions are needed. Urine and plasma porphyrins fall gradually with treatment, lagging behind but paralleling the fall in ferritin. The skin eventually becomes normal. After remission, further phlebotomy is needed only if there is a recurrence.
Low-dose chloroquine or hydroxychloroquine (100 to 125 mg po twice/wk) removes excess porphyrins from the liver by increasing the excretion rate. Higher doses can cause transient liver damage and worsening of porphyria. When remission is achieved, the regimen is stopped.
Chloroquine and hydroxychloroquine are not effective in advanced renal disease, and phlebotomy is usually contraindicated because of underlying anemia. However, recombinant erythropoietin mobilizes excess iron and resolves the anemia enough to permit phlebotomy. In end-stage renal disease deferoxamine is an adjunct to phlebotomy for reduction of hepatic iron, the complexed iron being removed during dialysis. Dialyzers with ultrapermeable membranes and extra high blood flow rates are needed.
Patients with overt PCT and HCV infection are preferentially treated with pegylated interferon-α2a and ribavirin. Previous iron depletion augments the response to antiviral therapy.
Children with symptomatic PCT are treated with small-volume phlebotomies or oral chloroquine; dosage is determined by body weight.
Skin symptoms occurring during pregnancy are treated with phlebotomy. In refractory cases, low-dose chloroquine can be added; no teratogenic effects have been recognized. Depending on degree of hemodilution and iron depletion, the skin symptoms usually improve with advancing pregnancy.
Postmenopausal estrogen supplementation is interrupted during treatment for PCT. Stopping estrogens often induces remission. After remission, estrogens can be reintroduced, preferentially in transdermal administration to reduce hepatic porphyrogenic exposure.
Prevention
Patients should avoid sun exposure; hats and clothing protect best, as do zinc or titanium oxide sunscreens. Typical sunscreens that block UV light are ineffective, but UVA-absorbing sunscreens, such as those containing dibenzylmethanes, may help somewhat. Alcohol ingestion should be avoided permanently, but estrogen supplementation can usually be resumed safely after a disease remission.
Erythropoietic
Protoporphyria
EPP typically
manifests in infancy with burning skin pain after even short exposure
to sunlight. Gallstones are common later in life, and acute liver
failure occurs in about 10%. Diagnosis is based on symptoms and
increased levels of protoporphyrin in RBCs and plasma. Treatment
is with β-carotene or dihydroxyacetone and avoidance
of sunlight. In patients with liver failure, combined liver and
bone marrow transplantation may be life saving as well as curative.
Etiology
EPP results from deficiency of the enzyme ferrochelatase in erythroid tissue. Clinical prevalence is about1/75 000. Phototoxic protoporphyrins accumulate in bone marrow and RBCs, enter the plasma, and are deposited in the skin or excreted by the liver into bile and stool. Heavy biliary protoporphyrin excretion can produce gallstones. These cytotoxic molecules sometimes damage the hepatobiliary tract, resulting in hepatic protoporphyrin accumulation that leads to acute liver failure; liver failure may become clinically acute within days.
Inheritance pattern is basically autosomal dominant but complex. Clinical manifestations occur only in people who have both the defective EPP gene and an unusual low-output (but otherwise normal) allele from the healthy parent.
Symptoms and Signs
Severity varies greatly, even among patients within a single family. Usually, an infant or young child with EPP cries for hours after even short exposure to sun. However, because cutaneous signs are usually absent and young children cannot describe their symptoms, EPP often goes undiagnosed.
If unrecognized, EPP causes psychosocial problems because children inexplicably refuse to go outdoors. The pain may be so distressing that it produces nervousness, tenseness, aggressiveness, or even feelings of detachment from the surroundings or suicidal thoughts.
In childhood, crusting may develop around the lips and on the back of the hands after prolonged sun exposure. Blistering and scarring do not occur. If skin protection is neglected, chronically, rough, thickened, and leathery skin may develop, especially over the knuckles. Linear perioral furrows (carp mouth) may develop.
Biliary excretion of large amounts of protoporphyrin can produce cholestasis that progresses to nodular cirrhosis and acute liver failure in ≤ 10% of patients; symptoms include jaundice, malaise, upper abdominal pain, and tender hepatic enlargement.
Diagnosis
EPP should be suspected in children and adults with painful cutaneous photosensitivity who experience no blisters or scarring. Family history is usually negative. The diagnosis is confirmed by finding increased RBC and plasma protoporphyrin levels. A genetic marker for susceptibility to cholestatic complications has been identified.
Screening of potential carriers among relatives is by demonstrating increased RBC protoporphyrin contents and decreased ferrochelatase activity (assayed in lymphocytes) or by genetic testing if the mutation has been identified in the index case. Susceptibility for cutaneous disease in carriers is indicated by finding the low-output ferrochelatase allele.
Treatment
Acute skin symptoms are alleviated by cold baths or wet towels, analgesics, and antihistamines. Regular physician-patient consultations that provide information, discussion, and opportunities for genetic counseling together with physical checkups are important.
Patients should avoid sun exposure; opaque titanium dioxide or zinc oxide sunscreens are beneficial, and UVA-absorbing sunscreens, such as those containing dibenzylmethanes, may help somewhat. Protection against the operating light is strictly required in liver transplantation to avoid serious phototoxic injury to inner organs. Covering of light sources with filters that block wavelengths < 470 nm is required. Endoscopy, laparoscopy and nontransplant abdominal surgery are not connected with risk for phototoxic damage.
Patients should avoid alcohol and fasting, both of which increase the rate of RBC production and thus the protoporphyrin load. Drugs that trigger acute porphyrias (see Table 4: Porphyrias: Drugs and Porphyria*) need not be avoided.
Systemic β-carotene produces slight yellow protective skin coloration and neutralizes the toxic radicals in the skin that cause symptoms. Dose depends on patient age (see Table 6: Porphyrias: Doses of β-Carotene in Erythropoietic Protoporphyria).
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Table 6
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Doses of β-Carotene
in Erythropoietic Protoporphyria
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Patient Age (yr)
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Dose (oral)
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1–4
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60–90 mg once/day
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5–8
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90–120 mg once/day
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9–12
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120–150 mg once/day
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13–16
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150–180 mg once/day
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> 16
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Up to 300 mg once/day*
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*To maintain serum levels of 11–15 μmol/L.
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Another antioxidant, cysteine, may also lessen photosensitivity. The brown protective skin color obtained with topically applied dihydroxyacetone is generally cosmetically preferable to the yellowish tint produced by β-carotene.
If the above-mentioned measures are ineffective (eg, patients have increasing photosensitivity, rising porphyrin levels, progressive jaundice), RBC hypertransfusion (ie, to above-normal Hb levels) can reduce the production rate of porphyrin-loaded RBCs. Administration of bile acids facilitates biliary excretion of protoporphyrin. Oral cholestyramine or charcoal interrupts the enterohepatic circulation. Liver failure may require immediate liver transplantation. Bone marrow exchange corrects the basic metabolic defect.
Patients with EPP should undergo annual surveillance for risks of cholestasis. Tests include RBC porphyrin levels, porphyrin excretion patterns, and liver function. Abnormal findings should be evaluated by a porphyria specialist and a hepatologist. If the liver appears involved, biopsy is done to identify progressive disease. Patients should be vaccinated against hepatitis A and B and advised to avoid alcohol.
Last full review/revision August 2008 by Stig Thunell, MD, PhD
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