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906 Part VI: The Erythrocyte Chapter 58: The Porphyrias 907

with type 1 or “sporadic” PCT have no UROD mutations and no family hepatocyte necrosis, inflammation, increased iron, and increased fat.
history of PCT. Approximately 80 percent of patients fall into this cate- Mild abnormalities in liver function tests, especially serum transami-
gory. Type 2 or “familial” PCT comprises approximately 20 percent of nases and γ-glutamyltranspeptidase, are present in almost all cases, but
cases who are heterozygous for UROD mutations; but because the pene- cirrhosis is unusual. The risk of hepatocellular carcinoma is increased,
trance of this trait is low there are usually no other documented cases in especially in those with more prolonged disease, cirrhosis, or other risk
the family. In families with type 3, which is rare, more than one member factors such as hepatitis C or alcoholic liver disease. 268–270
has PCT, but there is no UROD mutation; these familial cases presum- Excess porphyrins are transported in plasma from the liver. Skin
ably share other inherited or environmental susceptibility factors. histopathology includes subepidermal blistering and deposition of peri-
Although hepatic UROD activity must be reduced to approx- odic acid-Schiff–positive material around blood vessels and fine fibrillar
imately 20 percent of normal for PCT to be manifest, the amount of material in the upper dermis and at the dermoepithelial junction. Immu-
enzyme protein, when measured immunochemically in liver, remains at noglobulin G, other immunoglobulins, and complement are deposited
its genetically determined level, which in type 2 cases is approximately around dermal blood vessels and at the dermoepithelial junction. Splits
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50 percent of normal. Mice heterozygous for mutant UROD alleles in the lamina lucida of the basement membrane lead to formation of
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are much more sensitive to porphyrinogenic stimuli than wild-type fluid-containing bullae. These histologic changes are found in other
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animals. In heterozygous mice that display porphyric phenotypes, cutaneous porphyrias, as well as pseudoporphyria, and are not diagnos-
hepatic UROD protein is half normal, but the catalytic activity of the tic for PCT. Activation of the complement system after irradiation has
enzyme is reduced to approximately 20 percent, suggesting the exis- been demonstrated in PCT patients both in vivo and in vitro in sera,
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tence of an inhibitor of hepatic UROD. 261 and is thought to result from generation of reactive oxygen species.
Although iron does not directly inhibit UROD, there is consider- Susceptibility Factors PCT is a highly heterogeneous disease,
able evidence that PCT is an iron-related disease, with hepatic siderosis with multiple susceptibility factors expected in the individual patient.
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seen in many cases. This explains why HFE (hemochromatosis gene) Multiple factors are important in familial as well as sporadic PCT,
mutations that lead to increased intestinal iron absorption predispose because heterozygosity for a UROD mutation is a susceptibility factor
to development of PCT (Chap. 42). Individuals who inherit a UROD that does not of itself reduce hepatic enzyme activity sufficiently to
mutation have approximately 50 percent of normal enzyme activity cause the disease. The environmental, infectious, and inherited factors
from birth, such that a UROD inhibitor can more readily reduce enzyme discussed below, none of which is invariably present, are known or sus-
activity to less than approximately 20 percent of normal. How iron and pected to play an important role. Their prevalence may show consider-
other known or suspected susceptibility factors such as alcohol, smok- able geographic variation in PCT patients as well as healthy subjects.
ing, estrogens, hepatitis C, HIV, hepatic steatosis, and other suspected Alcohol PCT has long been associated with excess alcohol use.
factors contribute to the development of PCT is less-well understood, Alcohol and its metabolites may induce ALAS1 and CYP2E1, gener-
but these may act in part by increasing oxidative stress in hepatocytes. ate active oxygen species that contribute to oxidative damage, cause
A deficiency of ascorbic acid, 261a and perhaps other antioxidants, may mitochondrial injury, deplete reduced glutathione and other antioxi-
263
play a role in some patients. Smoking may also act by inducing hepatic dant defenses, increase production of endotoxin, activate Kupffer cells,
CYPs, including CYP1A2, which is essential for causing uroporphyria decrease the iron regulatory hormone hepcidin and increase iron
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in rodent models, 264,265 and may produce a UROD inhibitor, which has absorption.
been characterized as a uroporphomethene. This substance is a prod- Smoking and Cytochrome P450 Enzymes Smoking is less exten-
uct of partial oxidation of uroporphyrinogen, and is found in the liver sively studied as a risk factor but is commonly associated with alcohol
of mice that are heterozygous for a UROD mutation, homozygous for use in PCT. Smoking may increase oxidative stress in hepatocytes,
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62
an HFE mutation (C282Y), and develop uroporphyria spontaneously. and induces CYP1A2, which is essential to the development of uropor-
Other potential mechanisms for lowering of hepatic UROD activity in phyria in rodent models. CYP levels have been found to be increased in
PCT, such as oxidative damage to UROD active site residues, are less liver in human PCT, but it is not clear which CYP might be important in
favored but have not been excluded. 266 pathogenesis of the human disease. A study of caffeine metabolism did
At least 70 different UROD mutations have been identified in type not find evidence for increased CYP1A2 activity in vivo in PCT, even
2 PCT and HEP (see Table 58–1). These reduce UROD activity and when smokers and nonsmokers were analyzed separately. However, a
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immunoreactivity to approximately 50 percent of normal in all tissues more inducible polymorphism of CYP1A2 has been found to be more
from birth. Most are missense mutations, with each occurring in one or common in PCT than in normal subjects. 276
a few families. Homozygosity for a null UROD mutation is lethal in early Estrogens Estrogen use is very common in women with
neonatal life. Therefore, in HEP at least one of the mutant UROD alleles PCT. 273,277,278 In the past, some men developed the disease after treat-
must preserve at least some catalytic activity. Knowledge of the crystal ment of prostate cancer with estrogens. Female rats or males treated
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structure of UROD allows mapping of specific mutations and predic- with estrogens are more susceptible to development of chemically
tion of their impact on enzyme structure and function. Expression stud- induced uroporphyria than untreated males. The mechanism is not
279
ies in eukaryotic cells suggest that some mutations may destabilize the established, although estrogens can generate reactive oxygen species in
enzyme protein in a tissue-specific manner. 267 some experimental systems. 266
Hepatitis C Reported prevalence of hepatitis C in PCT has ranged
Pathogenesis of the Clinical Findings from 21 to 92 percent in various countries, and greatly exceeds the prev-
A distinctive feature of PCT is massive accumulation of porphyrins in alence of this viral infection in healthy subjects, which shows consider-
the liver. As a result, fresh hepatic tissue shows strong red fluorescence able geographic variation. Hepatitis C is associated with excess fat, some
on exposure to long-wave ultraviolet light. Microscopic, birefringent, iron accumulation, mitochondrial dysfunction, and oxidative stress in
needle-like inclusions are found in lysosomes, and paracrystalline inclu- hepatocytes, which may contribute to the development of PCT. Dysregu-
sions in mitochondria. Increased stainable iron is very common. Other lation of hepcidin may contribute to iron accumulation in hepatitis C. 280
nonspecific hepatic findings are probably partly a result of the disease Human Immunodeficiency Virus PCT is less commonly associ-
itself, although the effects of associated factors such as alcohol and ated with HIV infection than with hepatitis C. Occasionally PCT is
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hepatitis C are difficult to differentiate. Liver histopathology includes the initial manifestation of this infection. The mechanism is unknown.

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