Page 933 - Williams Hematology ( PDFDrive )

908 Part VI: The Erythrocyte Chapter 58: The Porphyrias 909

for CPO, leading to formation of dehydroisocoproporphyrinogen, anemia. Additional iron depletion is not beneficial, and causes anemia.
which is excreted in bile and undergoes oxidation by intestinal bacteria Treatment is also guided by plasma (or serum) porphyrin levels, which
to isocoproporphyrins. 292 are more convenient to measure repeatedly than urine porphyrins, and
Measurement of plasma porphyrins and determination of the fluo- fall more slowly than the serum ferritin. Plasma porphyrins usually
rescence emission peak at neutral pH is especially useful for screening decline from initial levels of 10 to 25 mcg/dL during treatment, to below
patients with blistering skin lesions. A substantial increase with a peak at the upper limit of normal (~1 mcg/dL) within weeks after phlebotomies
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approximately 620 nm is most commonly caused by PCT, and excludes are completed. New skin lesions are generally decreased at the end of
VP and pseudoporphyria, which are the most common conditions that treatment, but some may occur for a few weeks after plasma porphyrin
mimic PCT clinically. 292a Plasma porphyrin measurements are essential levels become normal. Severe sclerodermatous changes and liver func-
for diagnosis of PCT in patients with advanced renal disease; the ref- tion abnormalities can also improve.
erence range is higher in patients with renal failure than in normals. 293 After a remission, continued phlebotomies are generally not
Erythrocyte porphyrins are substantially increased in CEP and needed. However, relapses may occur, especially in patients who resume
HEP, but are normal or only modestly increased in PCT. Rare cases of use of alcohol, and are treated by another course of phlebotomies. For
HCP with blistering lesions are identified by a predominance of copro- patients with the C282Y/C282Y or C282Y/H63D HFE genotypes, man-
porphyrin III in urine and especially feces. Familial (type 2) cases are agement guidelines for hemochromatosis should be followed. Con-
identified by half-normal erythrocyte UROD activity or preferably by tinued phlebotomies as needed to maintain a serum ferritin below
DNA studies to identify a UROD mutation. Erythrocyte UROD activ- approximately 50 ng/mL may also be beneficial in patients who have
ity is 5 to 30 percent of normal in HEP, and DNA studies reveal that a experienced recurrences of PCT, although published experience is lim-
UROD mutation is inherited from each parent. ited. It is also advisable to follow porphyrin levels and reinstitute phle-
Biochemical findings in HEP resemble PCT, with predominant botomies promptly if porphyrin levels begin to rise. Liver imaging and a
accumulation and excretion of highly carboxylated porphyrins and iso- serum α-fetoprotein determination should be repeated as screening for
coproporphyrins. However, in contrast to PCT, erythrocyte zinc pro- hepatocellular carcinoma. After remission, transdermal estrogen can be
toporphyrin is substantially increased. At least one genotype may be resumed in women, if needed, with little risk for recurrence of PCT. 275
associated with predominant excretion of pentacarboxylporphyrin. 291 A low-dose regimen of hydroxychloroquine or chloroquine is also
effective, 266,298–303 and most appropriate when phlebotomy is contraindi-
Therapy cated or poorly tolerated, if iron overload is not severe. However, this
Treatment is highly effective but specific in both sporadic and familial treatment is preferred at some centers because it is more convenient
PCT, and therefore should be initiated only after the diagnosis is well and much less expensive. These 4-aminoquinoline antimalarials do
established. It is sometimes reasonable to start treatment after PCT is val- not appear to deplete hepatic iron, and the mechanism for their effect
idated with a plasma porphyrin screen and excludes VP and pseudopor- in PCT is not fully understood. Full therapeutic doses of these drugs
phyria (see “Diagnosis” above). Patients should be questioned and tested exacerbate photosensitivity in PCT, induce fever, malaise, and nausea,
for all known susceptibility factors, including use of alcohol, tobacco, markedly increase urinary and plasma porphyrins, and increase serum
and estrogens, hepatitis C, HIV, HFE mutations, and inherited UROD transaminases, other liver function tests, and ferritin. This reaction can
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deficiency (erythrocyte UROD activity or, preferably, UROD mutations), even unmask previously unrecognized PCT. Although these adverse
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because their presence influences management. Serum ferritin should be effects, which are unique to PCT, are followed by complete remission,
measured before starting treatment. Patients are advised to stop drink- they should be avoided by a low-dose treatment regimen (hydroxy-
ing and smoking and to discontinue estrogens. A nutritionally adequate chloroquine 100 mg or chloroquine 125 mg—one-half of a standard
intake of ascorbic acid and other nutrients should be assured, but this tablet—twice weekly) at least until plasma or urine porphyrins are
vitamin should not be administered as primary therapy. normalized. 298,301,302 However, some patients may respond poorly and
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Improvement may occur after removing one or more susceptibility require later treatment with larger doses, or phlebotomy. There is a
factor, but without phlebotomy or low-dose hydroxychloroquine recov- small risk of retinopathy, which may be lower with hydroxychloro-
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ery is unpredictable or slow. Repeated phlebotomy is the preferred quine. A recent prospective study found that time to biochemical
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treatment at most centers. The original rationale proposed by Ippen remission with low-dose hydroxychloroquine was comparable to that
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in 1961 was to decrease the commonly associated mild or moderately with phlebotomy. In a retrospective study, low-dose chloroquine was
increased hemoglobin, stimulate erythropoiesis, and perhaps channel ineffective in patients homozygous for the C282Y mutation of the HFE
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excess heme pathway intermediates to hemoglobin synthesis. How- gene, which suggests that the degree of excess hepatic iron may influ-
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ever, the oxidized porphyrins that accumulate in PCT cannot reenter ence response to this treatment.
the heme biosynthetic pathway and be converted to heme, and it is now These 4-aminoquinolines are not effective in other porphyrias, and
understood that phlebotomy is effective by reducing body iron stores do not mobilize all types of porphyrins from liver and other tissues.
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and liver iron content. Treatment with an iron chelator such as desferri- Chloroquine may form complexes with a variety of porphyrins, which
oxamine is less efficient than phlebotomies in reducing iron, but may be might promote their mobilization from liver, 310,311 but this does not
tried when the latter are contraindicated. 296 appear to explain the effects in PCT. It was suggested that mobilization
Approximately 450 mL of blood is removed, usually at 2-week of hepatic iron may be important, 302,312,313 but serum ferritin concentra-
intervals. In one series an average of 5.4 phlebotomies was required for tions do not change significantly during treatment. Most likely, these
remission, but many more are needed in some patients with coexist- drugs colocalize with excess porphyrins in lysosomes and other intra-
ing hemochromatosis and marked increases in serum ferritin levels. cellular organelles and promote their release by a process that involves
Hemoglobin or hematocrit levels are followed as safety (not therapeu- transient cell damage.
tic) targets, to prevent symptomatic anemia. Usually, the hemoglobin PCT may improve after treatment of coexisting hepatitis C. How-
should not fall below 10 to 11 g/dL, but the baseline value and the age ever, for several reasons PCT should be treated first and hepatitis C
and clinical condition of the patient are also considered. The therapeu- later in most cases. First, PCT is usually more symptomatic and can
tic target is a serum ferritin near 15 ng/mL, which is close to the lower be treated more quickly and effectively. Second, there is some evidence
limit of normal and associated with tissue iron depletion but usually not that treatment of hepatitis C may be more effective after iron reduction.

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