Page 930 - Williams Hematology ( PDFDrive )

904 Part VI: The Erythrocyte Chapter 58: The Porphyrias 905

blistering skin lesions identical to those seen in PCT. Cutaneous man- PPO are not widely available. DNA studies are most reliable for identi-
ifestations are much more common in VP than in HCP. The enzyme fying asymptomatic carriers, once the mutation affecting the family is
deficiency in each is inherited as an autosomal dominant trait with identified.
variable penetrance (see Table 58–1 and Fig. 58–1). As in AIP, most Harderoporphyria is a variant form of HCP that results from a
individuals who inherit the trait remain asymptomatic. Both disorders homozygous defect of a structurally altered CPO, such that hardero-
are less common and generally less severe than AIP in most countries. porphyrinogen is released prematurely from the enzyme. This variant is
The incidence of HCP was estimated to be 2 per 1,000,000 population identified by finding a predominance of harderoporphyrin in urine and
250
in Denmark, and the incidence of VP in Finland reported at 1.3 per feces. Neonatal hemolytic anemia is a distinctive feature of this condi-
258
100,000 population. 251 tion. Increases in porphyrin precursors and porphyrins may be more
Because of a founder effect, VP is especially common among whites severe in homozygous HCP and VP, with substantial increases in ery-
of Dutch descent in South Africa, where almost all cases share the same throcyte zinc protoporphyrin.
PPO mutation (R59W). The incidence of VP in that country was esti-
252
mated at 3 per 1000 population. Very rare cases of homozygous HCP Therapy
and VP are manifested by severe neurologic impairment early in life, The identification and avoidance of precipitating factors is essential.
but not acute attacks, and severe photosensitivity. 253 Treatment of acute attacks is the same as in AIP. Treatment of the
phototoxic manifestations is not satisfactory. Although the lesions are
Pathophysiology identical to the blistering skin lesions seen in PCT, there is no response
Like other porphyrias, HCP and VP are heterogeneous at the molecular in HCP and VP to phlebotomies or low-dose chloroquine or hydroxy-
level. At least 43 CPO mutations, mostly missense mutations, have been chloroquine. Therefore, avoidance of sunlight and use of protective
identified in HCP, and 130 PPO mutations in VP (see Table 58–1). clothing is most important. Yearly screening for hepatocellular carci-
254
Clinical expression is variable and onset of neurologic manifestations is noma by imaging is recommended after age 50 years, especially in indi-
influenced by the same factors that are important in AIP. viduals with persistent increases in porphyrin precursors or porphyrins.
CPO catalyzes the two-step decarboxylation of coproporphyrin-
ogen III to yield protoporphyrinogen IX, with intermediate formation PORPHYRIA CUTANEA TARDA AND
of harderoporphyrinogen, a tricarboxyl porphyrinogen. A single active
site carries out both decarboxylations, and most of the harderoporphy- HEPATOERYTHROPOIETIC PORPHYRIA
rinogen formed is not released before being further decarboxylated Definition
to protoporphyrinogen IX. However, a variant form of HCP, termed PCT is caused by a deficiency of hepatic UROD activity and is mani-
harderoporphyria, is a result of CPO mutations that favor premature fested by the development of chronic, blistering skin lesions on the dor-
release of harderoporphyrinogen from the enzyme. 255 sal aspects of the hands and other sun-exposed areas of skin in middle
or late life. This iron-related disorder is the most common and readily
Clinical Features treated form of porphyria (see Table 58–1 and Fig. 58–1). The enzyme
Neurovisceral manifestations are identical to those in other acute por- deficiency develops specifically in the liver as a result of generation of
phyrias. Although both HCP and VP are generally less severe than AIP, a UROD inhibitor in the presence of multiple susceptibility factors.
attacks may be life-threatening. Blistering skin lesions may be seen, and The disease has been classified as types 1 to 3, based on the presence or
are much more common in VP than in HCP. Factors that contribute absence of heterozygous UROD mutations and other unknown inher-
to attacks, including drugs, hormones, and dietary factors, are also the ited factors. Patients with familial (type 2) PCT are heterozygous for
same as in AIP. Oral contraceptives may precipitate cutaneous manifes- UROD mutations, which are inherited as an autosomal dominant trait
tations of VP. Risk of chronic hypertension, renal disease, and hepatoc- with low penetrance. HEP is the homozygous (or compound heterozy-
ellular carcinoma are increased, as in AIP. gous) form of familial (type 2) PCT, which usually presents in child-
hood and resembles CEP clinically. Rarely, hepatocellular carcinomas
Diagnosis may secrete porphyrins and simulate PCT; however the enzyme defect
Urinary PBG is elevated during acute attacks, and usually is the basis was not established in such cases. 259
for diagnosis of these acute porphyrias. However, increases in PBG may PCT must be differentiated from other porphyrias that cause iden-
be less than in AIP, and more transient. Levels of coproporphyrin III tical blistering skin lesions and from pseudoporphyria (also known as
are markedly increased in urine and feces, whereas in AIP fecal por- pseudo-PCT). The latter is a poorly understood condition that presents
phyrins are normal or only slightly increased. Fecal porphyrins in HCP with lesions that closely resemble PCT, but with plasma porphyrins that
are almost entirely coproporphyrin III, whereas in VP both copropor- are not significantly increased. Potentially photosensitizing drugs, such
phyrin III and protoporphyrin are approximately equally increased. The as nonsteroidal antiinflammatory agents, are sometimes implicated.
fecal coproporphyrin III:I ratio is sensitive for diagnosis of HCP, even
in asymptomatic stages of the disease. Plasma porphyrin concentra- Pathophysiology
256
tion is commonly increased in VP, seldom increased in HCP unless UROD sequentially decarboxylates uroporphyrinogen (which has eight
there are cutaneous manifestations, and are normal or only slightly carboxyl side chains) to yield coproporphyrinogen (with four carboxyl
increased in AIP. A characteristic plasma porphyrin fluorescence max- groups). When hepatic UROD is profoundly inhibited, the substrate
imum observed at neutral pH is a very specific marker for VP, and is and the intermediate and final products of the reaction accumulate as
believed to represent protoporphyrin bound covalently to plasma pro- the oxidized porphyrins in the liver (mostly uroporphyrin and hepta-
teins. The fluorescence maximum as at approximately 626 nm in VP, carboxylporphyrin), and then appear in plasma and urine. Photosen-
257
approximately 634 in EPP, and approximately 620 in other porphyrias. sitivity results from activation of porphyrins in the skin by long-wave
This fluorometric method is more effective than examination of fecal ultraviolet light and generation of reactive oxygen species.
257
porphyrins for detecting asymptomatic VP, and is useful for rapidly Hepatic UROD activity is inhibited to less than approximately 20
differentiating VP and PCT. Erythrocyte PBG deaminase activity is nor- percent of normal in all patients with PCT. Types 1, 2, and 3 are not fun-
mal in HCP and VP, and usually deficient in AIP. Assays for CPO and damentally different or clinically distinguished from each other. Patients

Kaushansky_chapter 58_p0889-0914.indd 905 9/18/15 5:58 PM