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898 Part VI: The Erythrocyte Chapter 58: The Porphyrias 899

Mild anemia with microcytosis, hypochromia, reduced iron stores, metal-free or total protoporphyrin. At this writing, we are aware of only
but usually normal serum iron, and serum transferrin receptor-1, is two laboratories in the United States (Mayo Clinic Laboratories and the
a common feature of EPP, 115,128,129,130,131 but there is little evidence for Porphyria Laboratory at the University of Texas Medical Branch), that
impaired erythropoiesis or abnormal iron metabolism, 129,130 and hemo- reliably report the amounts of total, metal-free, and zinc protoporphy-
lysis is absent or very mild. 131,153 Iron accumulation in erythroblasts and rin, as is needed for confirmation of a diagnosis of EPP. The proportions
132
ring sideroblasts have been noted in marrow in some patients. Find- of metal-free and zinc protoporphyrin can also usually distinguish XLP
ings in XLP are similar. Also, iron is proposed to have a role in splicing (50 to approximately 85 percent metal-free protoporphyrin) from EPP
of FECH mRNA, where decreased iron leads to an increase in incor- (>85 percent metal-free protoporphyrin).
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rect splicing of the mRNA. Binding of iron-responsive elements bind- The plasma porphyrin concentration is almost always at least
ing proteins (IRPs) to the 5′-iron-responsive element (IRE) in ALAS2 mildly increased in EPP, but often less than in other cutaneous por-
mRNA, in low iron conditions, prevents translation of ALAS2 mRNA. phyrias, and may be normal in mild cases. Plasma porphyrins in EPP
When iron is supplemented, the IRPs no longer have high affinity for the are particularly subject to photodegradation during sample processing
ALAS2 5′-IRE, leading to increased translation, import into the mito- unless great care is taken to shield the sample from natural or fluores-
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chondria, and enhanced production of ALA. 134 cent light. For these reasons, measurement of erythrocyte rather than
Precipitating factors that are important in the hepatic porphy- plasma porphyrin should be relied upon for diagnosis of EPP and XLP.
rias do not appear to play an important role in EPP. Although more Fecal porphyrins are normal or somewhat increased, and consist
long-term followup studies are needed, porphyrin levels and symptoms mostly of protoporphyrin. Urine porphyrins are normal, except after
typically do not change over time, unless liver dysfunction develops. hepatopathy develops, which causes increases in urinary coproporphy-
Concurrent iron deficiency or other marrow problems might also lead rin as is typical for other forms of liver diseases.
to further increases in porphyrin levels and photosensitivity. Pregnancy
is reported to lower erythrocyte protoporphyrin levels somewhat and Therapy
increase tolerance to sunlight. 135 Avoidance of the sunlight exposure is important, and often requires
Neurovisceral manifestations are absent in uncomplicated EPP. changes in lifestyle and the working environment. Topical sunscreens
Patients with severe protoporphyric hepatopathy may develop a severe that absorb ultraviolet A and sunblocks containing zinc oxide or tita-
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motor neuropathy similar to that seen in the acute porphyrias. Auto- nium dioxide may be helpful. Orally administered β-carotene, which
somal recessive EPP associated with palmar keratoderma has also been probably quenches activated oxygen radicals, 143,144 may afford some
associated with unexplained neurologic symptoms. 111 protection after 1 to 3 months of therapy, but results are variable. A
Gallstones containing large amounts of protoporphyrin are com- daily dose of 120 to 180 mg or higher is recommended to achieve a
mon, and may require cholecystectomy at an unusually early age. Liver serum β-carotene level of 600 to 800 mcg/dL. Oral cysteine may also
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127
function and liver protoporphyrin content are usually normal in EPP. quench excited oxygen species and increase tolerance to sunlight in
Protoporphyric hepatopathy, which is the most life-threatening com- EPP. Other treatments that aim to either increase skin pigmentation
145
plication of EPP, results from the cholestatic effects of protoporphyrin or scavenge activated oxygen species have been reviewed and include
144
presented in excess amounts to the liver. It can be the major presenting dihydroxyacetone/Lawsone, vitamin C and narrow-wave ultraviolet B
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feature of EPP, and may be chronic or progress rapidly to death from phototherapy to increase melanin. Afamelanotide, an α-melanocyte–
146
liver failure. Unnecessary surgery for suspected biliary obstruction can stimulating hormone analogue that increases skin melanin, has shown
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be detrimental and should be avoided. Operating room lights during benefit in clinical trials. 147
liver transplantation or other surgery, especially in patients with hepato- It is advisable to monitor liver function tests at least yearly, and
pathy, can cause marked photosensitivity with extensive burns of the avoid severe caloric restriction and drugs or hormone preparations that
skin and peritoneum and photodamage of circulating erythrocytes. 139 impair hepatic excretory function. 148,149 Because iron deficiency might
be detrimental by further limiting heme synthesis and increasing pro-
Diagnosis toporphyrin accumulation, ferritin levels should be followed in EPP
Painful, nonblistering photosensitivity suggests the diagnosis. A sub- and XLP patients, keeping in mind that ferritin in the lower part of the
stantial elevation of erythrocyte protoporphyrin is expected, but is not normal range (especially for women) may indicate depleted iron stores.
specific, as erythrocyte zinc protoporphyrin is predominantly increased Iron supplementation has been reported to worsen photosensitivity in
in conditions such as homozygous porphyrias (other than most cases some cases (although increases in protoporphyrin levels were not docu-
140
of CEP), iron deficiency, lead poisoning, anemia of chronic disease, mented) and to correct microcytosis without increasing porphyrin levels
141
hemolytic conditions, and many other erythrocyte disorders. A in others. Therefore, at present iron supplementation in EPP and XLP is
unique finding in EPP is increased erythrocyte protoporphyrin with controversial, and systematic studies are needed. Because patients avoid
a predominance of metal-free rather than zinc protoporphyrin. This sunlight exposure, vitamin D supplementation is recommended.
occurs because FECH, which can utilize metals in addition to iron, Management of protoporphyric liver disease is difficult. The condi-
catalyzes the formation of zinc protoporphyrin, and this activity is tion may resolve spontaneously especially if another reversible cause of
deficient in EPP. Because FECH is not deficient in XLP, erythrocytes liver dysfunction, such as viral hepatitis or alcohol, is contributing. 122,150
153
contain increased amounts of both zinc and metal-free protoporphyrin, Cholestyramine, 124,151,152 ursodeoxycholic acid, vitamin E, red blood
154
although the latter still predominates in most cases. cell transfusions, plasma exchange, and intravenous hemin may be
Consequently, the diagnosis of EPP requires demonstration of an given in combination to bridge patients until liver transplantation or
155
increase in metal-free protoporphyrin in red cells. Amounts of metal- there is spontaneous improvement. Success of liver transplantation
free and zinc protoporphyrin in erythrocytes can be measured by etha- is comparable to that in other liver diseases, even though protoporphy-
nol or acetone extraction or high-performance liquid chromatography. ric hepatopathy may recur in the new liver, a result of the continued
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There is confusion about terminology used by different laboratories. erythrocyte protoporphyrin release by the marrow. Acute motor neu-
For example, the term “free erythrocyte protoporphyrin,” refers to pro- ropathy has developed in some patients with protoporphyric liver dis-
toporphyrin results measured with a hematofluorometer as an indicator ease after transfusion or liver transplantation, 158,159 and is sometimes
157
of lead exposure, but actually refers to zinc protoporphyrin rather than reversible. 158

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