URO-D is a 42 kDa polypeptide, the gene for which is located on
chromosome 1. Sporadic (type I) PCT, which accounts for approximately 80%
of cases, has normal gene expression, but the specific hepatic enzymatic
activity of URO-D is reduced by 60% (3).
In familial (type II) PCT, there are a variety of autosomal dominantly
inherited gene abnormalities that display a low penetrance (4).
There is some evidence for a putative third type of PCT that appears to be
a familial form of type I PCT (5,
6).
Finally, there is a toxic form of PCT in which exposure to aromatic
hepatotoxic hydrocarbons results in a cutaneous eruption similar to that
of sporadic PCT; this forms the basis of an animal experimental model for
PCT (7).
Abnormal iron metabolism in PCT has been long observed (8),
and in 1970, Lundvall clearly demonstrated significant iron storage in the
livers of 30 patients with PCT (9).
Hepatic siderosis and steatosis are commonly observed in PCT, whereas
cirrhosis is less common and is seen in around 10% of cases. There may be
an increased risk of hepatocellular carcinoma in patients with PCT (10,
11,
12).
Alcohol-related liver disease and chronic hepatitis C virus (HVC)
infection also are associated with PCT.
Hereditary hemochromatosis (HH) is a common disease of excess iron
storage in target organs, such as the liver, heart, and pancreas (13).
In 1976, a strong association was established between HH and HLA-A3 (14).
As the hepatic siderosis of PCT and HH appeared similar, investigators
screened PCT patients for the HLA allelic markers. It was postulated that
there may be a common genetic abnormality that could explain the iron
overload in PCT patients.
In 1985, Kuschner et al. reported a single family pedigree
that appeared to support a link with sporadic PCT and HLA-A3 (15).
Fifty-seven percent of their patients with sporadic PCT were HLA-A3
positive. Subsequent investigators both reaffirmed and contradicted this
observation (16,
17,
18,
19,
20).
Thus, the issue of a common gene defect in HH and PCT remained unanswered.
In 1996, Feder et al. described a candidate gene for HH (termed
the HFE gene) (21).
A homozygous single point mutation of the HFE gene (G to A at
nucleotide 845, causing a cysteine to a tyrosine substitution at residue
282, C282Y) occurs in 80-100% of patients with HH of predominantly
northern European ancestry but is less frequent in southern Europeans. The
allelic frequency in a Celtic-derived population is of the order of 14%
(22).
For other ethnic groups it is much less and is said to be absent in Asian,
African, and non-Caucasian American groups. A second mutation (C to G at
nucleotide 187, causing a histidine to aspartate substitution at residue
63 (H63D) has an allelic population frequency of 15-20%. However, this
mutation alone does not appear to have a role in the phenotypic expression
of HH, but when combined with the C282Y mutation (C282Y/H63D compound
heterozygote), it can lead to iron overload pathology (23).
The frequency of the C282Y and H63D mutations in patients with PCT was
subsequently examined. Roberts et al. demonstrated that 44% of
patients with PCT carried at least one C282Y mutation compared with 11% of
controls (24).
They found no difference in the incidence of the H63D mutation between
patients and controls. Santos et al. described a similar incidence
of the C282Y mutation in 15 PCT patients, but a 23% incidence of the H63D
mutation in PCT patients compared with 4% of controls (25).
The prevalence of C282Y and H63D mutations in Australian patients with PCT
was similar to that described by Roberts (26).
Italian patients with PCT that had previously shown a strong HLA-A3
linkage in 1996, demonstrated no increased incidence of the C282Y
mutation, but did show an increased incidence of the H63D mutation (27).
In this issue of The American Journal of Gastroenterology,
Martinelli et al. report their findings of HFE gene
mutations in a cohort of Brazilian patients (28).
They found a 17.4% incidence of the C282Y mutation in 23 patients with
sporadic PCT, compared with 4% in controls. Interestingly, they found no
increased incidence of the H63D mutation, which is more in keeping with
the findings in groups studying patients of a Northern European ancestry.
It is well described that phenotypic expression of PCT is aggravated by
external agents, such as alcohol, estrogens, or HCV infection. There are
conflicting results relating to the prevalence of HCV infection in
patients with PCT. Patients with PCT from southern Europe have a high
prevalence of antibodies to HCV, whereas PCT patients from northern Europe
have low prevalence of HCV antibody positivity (29).
The current study has shown that 65.5% of the PCT patients in Brazil were
positive for antibody to HCV.
How do HFE gene mutations or HCV infection influence the
pathophysiology of sporadic PCT? It is likely that iron or HCV infection
affect hepatocyte URO-D activity. The importance of iron is clearly
demonstrated by the beneficial effect that venesection has on the course
of PCT. Furthermore, there is an increased incidence of PCT in South
African populations, which also have a high incidence of iron overload.
Elder postulates that URO-D inactivation is in part an iron-dependent
process (30).
Neither ferrous nor ferric forms of iron have a direct effect on URO-D.
However, in vitro studies show that iron-dependent hydroxyl radical
generating systems oxidize uroporphyrinogen into products that inhibit
URO-D. In toxic PCT, hydrocarbons may induce the activity of a cytochrome
P450 family that oxidizes uroporphyrinogen; this process has been shown to
be promoted by iron. It has also been postulated that iron induces the
activity of ALA-synthetase which would promote the accumulation of
uroporphyrins (see references within 30).
The exact function of the HFE gene has yet to be determined;
however, there is accumulating evidence to show that it does have a direct
physiological role in iron absorption and thus, when dysfunctional, leads
to the pathology seen in HH (23).
In susceptible individuals hepatocytes may become iron loaded, and URO-D
activity is inhibited.
The relationship of HCV infection to disturbances in iron metabolism is
far more uncertain. Current emphasis has concentrated on the effect that
iron has on the infected hepatocyte and hepatic immune function. It is
accepted that iron-loaded patients with HCV infection have a less
favorable outcome and are less responsive to antiviral therapies (31).
What remains uncertain is whether the iron loading is a consequence of
infection, or a host independent factor that leads to a more severe
outcome. Pro-inflammatory cytokines produced as a result of HCV infection
could alter hepatic iron metabolism. The observation that Northern
European PCT patients have a high prevalence of the C282Y mutation yet low
HCV positivity, with the converse observation in Southern European PCT
patients, reinforces the suggestion that the final insult to URO-D is an
increase in intracellular iron.
The paper by Martinelli et al. reaffirms previous findings that
the C282Y mutation or HCV infection may increase susceptibility to the
phenotypic expression of PCT. Efforts should now be focused on the effect
iron has on the clinical expression of PCT and how other promoting factors
act.
aRoyal Defence Medical College, Gosport,
United Kingdom
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Reprint requests and correspondence: A/Professor John K. Olynyk,
M.D., University Department of Medicine, Fremantle Hospital, P.O. Box 480,
Fremantle 6959, Western Australia, Australia.
Received Aug. 28, 2000; accepted Aug. 30, 2000.
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