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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1565-1571
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Medicine, Pharmacology, and
Pathology, the University of Utah School of Medicine, and the Latter
Day Saints Hospital, Salt Lake City, UT.
Inherited and acquired factors have been implicated in the
pathogenesis of porphyria cutanea tarda (PCT), a disorder characterized by a photosensitive dermatosis and hepatic siderosis. This study, comprising 108 patients with PCT, was intended to define the role of
hemochromatosis gene (HFE) mutations in the expression of PCT and to determine the contribution of acquired factors including alcohol, hepatitis C virus (HCV), and estrogen. The 2 known HFE mutations, cysteine 282 tyrosine (Cys282Tyr)
and histidine 63 asparagine (His63Asp), were detected by
polymerase chain reaction, and anti-HCV immunoglobulin G was detected
serologically. Liver biopsies were graded for iron content,
inflammation, and fibrosis. Estimates of alcohol and estrogen use were
based on a questionnaire. Of the PCT patients tested, 19% were
homozygous for the Cys282Tyr mutation; controls were equal to
0.5%. The compound heterozygous genotype was detected in 7% of the
PCT patients; controls were less than 1%. The transferrin saturation,
serum ferritin, and liver iron burden of all PCT patients were higher
than those of nonporphyric controls. The highest values were found in
PCT patients homozygous for the Cys282Tyr mutation. Of the
patients studied, 59% were HCV positive (compared with 1.8% of the
population), and 46% consumed more than 70 g of alcohol daily. Of the
female patients, 63% were ingesting estrogens. Hepatic damage was most marked in patients with the Cys282Tyr/Cys282Tyr genotype who
had HCV and drank heavily. Homozygosity for the Cys282Tyr
mutation and HCV are the greatest risk factors for expression of PCT,
and in most patients, more than 1 risk factor was identified. It was common for patients with HCV to consume alcohol. Patients with PCT
should be screened for HFE mutations and for HCV.
(Blood. 2000;95:1565-1571)
Porphyria cutanea tarda (PCT) is the most common type
of porphyria in humans. Estimates of prevalence have ranged from 1 in 5000 to 25 000 people.1 PCT is characterized clinically by a photosensitive dermatosis associated with skin fragility and blistering. The cutaneous photosensitivity is mediated by uroporphyrin and partially decarboxylated porphyrins. The source of these compounds is the liver, where the activity of uroporphyrinogen decarboxylase (URO-D) is diminished. These compounds accumulate in the liver, circulate in plasma, and are excreted in the urine.2
Two variants constitute virtually all cases of PCT in adults. Familial
PCT (F-PCT) is transmitted as an autosomal dominant trait and accounts
for about one-third of cases.2,3 Many URO-D mutations have been identified in
patients with F-PCT.4-6 The activity of URO-D is half
normal in all tissues, although porphyrins accumulate only in the
liver. Most carriers of mutant URO-D alleles do not express a
clinical phenotype unless additional factors are present. Sporadic PCT
(S-PCT) accounts for approximately two-thirds of cases.2 In
S-PCT, the decrease in activity of URO-D is restricted to the
liver, and no mutations in the URO-D gene have been
identified.7 The concentration of URO-D protein in the
liver is normal even though enzyme activity is reduced, which suggests
the presence of an enzyme inhibitor.8 Because rare
pedigrees have been reported, with several members displaying signs and
symptoms of S-PCT, a genetic factor other than a URO-D mutation
may be involved.9
The term PCT was first suggested by Waldenström10 in
1937 to distinguish this form of porphyria from the rare
photomutilating congenital erythropoetic porphyria (Gunther's
Disease). The association of liver disease, particularly alcoholic
liver disease, and PCT was recognized by Brunsting et al.11
by 1951. Iron was implicated in the pathogenesis of PCT based on the
nearly uniform finding of hepatic siderosis12 and the
beneficial effects of therapeutic phlebotomy.13,14 Edwards
et al.15 first suggested that hemochromatosis gene
mutations were responsible for the hepatic siderosis in many patients
with PCT. This suggestion was later confirmed by mutational analysis of
the hemochromatosis gene.16 The introduction of medicinal
estrogen for postmenopausal replacement therapy and contraception led
to an increase in the incidence of PCT in women and the recognition
that oral estrogens could induce clinical expression of
PCT.17 The discovery of the hepatitis C virus (HCV) and the
development of serologic and molecular diagnostic tests revealed an
association between HCV-induced liver disease and PCT, but the
prevalence of HCV infection in patients with PCT varies widely from
country to country.18
We studied 108 patients with PCT at the General Clinical Research
Center of the University of Utah. We report here the relative roles of
hemochromatosis gene (HFE) mutations, HCV, alcohol, and estrogens as risk factors for disease expression.
Informed consent
Diagnosis
Urine porphyrin determinations Urine porphyrins were quantified spectrophotometrically3 and by high-performance liquid chromatography (HPLC).21,23Blood tests of iron stores The serum iron concentration and transferrin saturation were measured as previously described.24 When possible, samples were obtained after subjects had fasted overnight. Serum ferritin concentrations were measured with radioimmunoassay kits (Ramco Laboratories, Houston, TX).Liver biopsies Hepatic iron stores were assessed by light microscopy (graded on a scale of 0 to 4) according to the method of Scheuer et al.25 and by atomic absorption spectrophotometry.24 The normal value for hepatocellular stainable iron is grade 0 to 1. Normal values for hepatic iron concentration are less than 25 µmol/g dry weight.19 Histologic grading and staging of HCV was performed by the method of Batts and Ludwig.26 Grading is a measure of the severity of the necroinflammatory process, and staging refers to the degree of fibrosis present.HCV antibody Anti-HVC IgG (immunoglobulin G) was detected serologically using a commercially available enzyme-linked immunoabsorbent assay (ELISA 2.0, Chiron, Emeryville, CA). A positive result is designated HCV+ and a negative result HCV .
HFE genotyping DNA was available from 87 patients with PCT (64 with S-PCT and 23 with F-PCT) and from 56 clinically normal subjects married to members of well-characterized hemochromatosis pedigrees.19,20 The ancestral cysteine 282 tyrosine (Cys282Tyr) HFE mutation and the histidine 63 asparagine (His63Asp) mutation were detected using polymerase chain reaction (PCR) amplification as described by Feder et al.27Estimation of alcohol intake Alcohol consumption was estimated with a questionnaire and graded as follows: grade 0: nondrinkers; grade 1: consumption of less than 20 g of alcohol per day; grade 2: consumption of between 20 g and 70 g of alcohol per day for a minimum of 3 consecutive years; grade 3: consumption of more than 70 g of alcohol per day for a minimum of 3 consecutive years.Statistics Statistical analyses were performed using the Prophet computer software package.28 Serum iron, transferrin saturation, and serum ferritin concentration values in PCT patients were compared to age- and sex-matched controls with the Wilcoxon signed rank test. Frequencies of the HFE genotypes were compared with the Fisher exact test. To calculate an odds ratio for the genotype Cys282Tyr/Cys282Tyr as a risk factor for PCT, we assumed the frequency of the homozygous mutant genotype among controls to be 0.005.27,29 The Mantel-Haenszel test was used to calculate an odds ratio for alcohol, HCV, and estrogens in PCT patients with the Cys282Tyr/Cys282Tyr genotype. We employed age- and sex-matched controls with hemochromatosis but without PCT who were members of well-characterized hemochromatosis pedigrees.19 We used 3 controls matched by age (plus or minus 5 years) and sex for each patient with PCT.
Individuals studied We evaluated 108 patients with PCT from 1977 to 1998. Of these patients, 31 (29%) had F-PCT and 77 (71%) had S-PCT. The F-PCT patients were members of 30 pedigrees. There were 18 males (mean age, 35 years) and 13 females (mean age, 45 years); 3 F-PCT patients were children: 2 brothers aged 6 and 10 years and an unrelated 12-year-old girl. The 2 clinically affected young brothers also had a clinically affected paternal uncle (not studied by us). This was the only F-PCT pedigree we evaluated with more than 1 clinically affected member. Of the 77 patients with S-PCT, 50 were males (mean age, 43 years), and 27 were females (mean age, 43 years). We found 2 siblings with S-PCT, a 53-year-old woman and her 49-year-old brother. Both also had hemochromatosis. Both alleles of URO-D were sequenced in these siblings, and no mutations were identified (data not shown). One female S-PCT patient was 5 years old.The iron phenotype Of the 108 patients with PCT, 9 had initiated phlebotomy therapy prior to our evaluation. The iron phenotype of the remaining 99 patients and 99 controls matched by age and sex is shown in Table 1. No significant differences in the iron phenotype were detected when patients with S-PCT were compared to patients with F-PCT. Values for the serum iron, transferrin saturation, and serum ferritin concentration in patients with PCT were significantly higher than in controls (Table 1). Hepatic parenchymal cell stainable iron was graded on 89 liver biopsies (60 obtained from males and 29 from females). Only 1 patient had no histologic evidence of hepatocellular iron stores (grade 0), yet her porphyria improved with phlebotomy therapy. This patient, a 27-year-old nulliparous woman with active systemic lupus erythematosus, was ingesting birth control pills at the time PCT developed. She did not drink alcohol and had no evidence of HCV. Liver biopsies from the remaining patients were graded for iron as follows: grade 1: 30 patients; grade 2: 37 patients; grade 3: 14 patients; and grade 4: 7 patients. The hepatic iron concentration measured by atomic absorption spectrophotometry was normal in the single subject with grade 0 liver iron and in 10 of the 30 patients with grade 1 liver iron.
Genotyping at the HFE locus HFE genotypes for 87 patients with PCT are shown in Table 2; 19 patients were Cys282Tyr homozygotes. Only 17 of these patients are shown in the table, as 2 pairs of Cys282Tyr homozygous siblings were evaluated; 1 sibling pair had F-PCT, and 1 pair had S-PCT. Homozygosity for the Cys282Tyr mutation was clearly overrepresented. The controls had the same frequency of heterozygosity for the Cys282Tyr mutation. Compound heterozygotes for the Cys282Tyr/His63Asp mutations also were overrepresented, but the number of subjects with this genotype was small. Of the 87 PCT patients included in Table 2, 174 chromosomes are represented. The Cys282Tyr mutation was carried in 53 (30%) of these 174 chromosomes compared with 7 (6%) out of 112 chromosomes (6%) in 56 nonporphyric Utah controls (P < .0001).
Correlation of the iron phenotype with the HFE genotype The hepatic iron concentration, transferrin saturation, and the serum ferritin concentration were highest in PCT patients who were homozygous for the Cys282Tyr mutation (Table 3). Regardless of the HFE genotype, patients with PCT had a higher transferrin saturation and serum ferritin concentration than the controls. The mean liver iron grade and transferrin saturation associated with compound heterozygosity at the HFE locus (Cys282Tyr/His63Asp) were higher than those in simple heterozygotes (Cys282Tyr/WT), but statistical significance could not be established because of the small number of compound heterozygotes.
Hepatitis C virus Serologic testing for anti-HCV IgG was performed on 71 patients with PCT. There were 42 (59%) seropositive (HCV+) patients. Males were more likely to be HCV+ (36/45 [80%]) than females (6/26 [23%]). There was no significant difference in the frequency of HCV+ between patients with S-PCT (35/56 [63%]) and those with F-PCT (7/15 [47%]) (P = .3). Of the 42 HCV+ patients, 27 (64%) had used intravenous drugs in the past, and 1 patient had received blood transfusions following an automobile accident 17 years before PCT developed. There was no significant difference in the frequency of HCV+ in PCT patients with any HFE genotype, nor was the iron phenotype influenced by HCV status.
Alcohol
Estrogens Of the 38 adult women with PCT, 24 (63%) were using oral estrogen preparations when PCT was first detected. None were using transdermal estrogen delivery systems. Of the 13 premenopausal women, 9 (60%; mean age, 33 years plus or minus 9 years) had been taking oral contraceptives for more than 6 months (range, 0.5-15 years). Of the 25 postmenopausal women, 15 (60%) were taking oral estrogen replacement therapy for more than 1 year (range, 1-20 years). In the premenopausal group, there were 7 women with S-PCT and 2 with F-PCT. In the postmenopausal group, there were 10 women with S-PCT and 5 with F-PCT. Estrogen ingestion was the only identified factor known to be associated with PCT in 9 women (7 with S-PCT and 2 with F-PCT). Five of these women had prominent hepatic steatosis; 1 had estrogen-induced hepatic adenomas, but the porphyrin content of a biopsy specimen taken from the adenoma did not differ from a sample from a normal portion of the liver (data not shown). We compared serum iron concentration, transferrin saturation, serum ferritin concentration, liver iron grade, and HCV status between women with PCT who were taking estrogens and those who were not. No significant differences were noted (data not shown).Associations between risk factors for PCT The Cys282Tyr/Cys282Tyr genotype was clearly a risk factor for the development of PCT (odds ratio of 60; 95% confidence limits (CLs), 18.5 and 195.7). To estimate the role of risk factors, such as HCV, alcohol, and estrogens, in Cys282Tyr homozygotes, we compared Cys282Tyr homozygotes with PCT to age- and sex-matched Cys282Tyr homozygotes without PCT (Table 5). Homozygotes for the Cys282Tyr mutation with grade 3 alcohol consumption had higher ferritin values and liver iron content than alcohol abusers who were not homozygotes.
Mutations at the HFE locus, HCV infection, excess alcohol intake, and exposure to estrogens all proved to be risk factors for the development of PCT. HFE mutations and HCV infection imparted the greatest relative risk, and the presence of multiple risk factors was more frequent than the presence of single risk factors.
Submitted July 18, 1999; accepted October 27, 1999.
Supported by grants RO-1 DK20503, RO-1 DK20603, MO-1 RR00064, P-50 DK49219, P-30 CA42014, and T-32 07115 from the National Institutes of Health, Bethesda, MD.
Reprints: James P. Kushner, General Clinical Research Center, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132; e-mail: james.kushner{at}hsc.utah.edu.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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  A. K. Aarsand, H. Boman, and S. Sandberg Familial and Sporadic Porphyria Cutanea Tarda: Characterization and Diagnostic Strategies Clin. Chem., April 1, 2009; 55(4): 795 - 803. [Abstract] [Full Text] [PDF]
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 R. S. Ajioka, J. D. Phillips, R. B. Weiss, D. M. Dunn, M. W. Smit, S. C. Proll, M. G. Katze, and J. P. Kushner Down-regulation of hepcidin in porphyria cutanea tarda Blood, December 1, 2008; 112(12): 4723 - 4728. [Abstract] [Full Text] [PDF]
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 J. D. Phillips, H. A. Bergonia, C. A. Reilly, M. R. Franklin, and J. P. Kushner A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda PNAS, March 20, 2007; 104(12): 5079 - 5084. [Abstract] [Full Text] [PDF]
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 J. P. Kushner, M. R. Franklin, C. P. Reilly, H. A. Bergonia, and J. D. Phillips An Inhibitor of Uroporphyrinogen Decarboxylase (URO-D) Causes Porphyria Cutanea Tarda (PCT). Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 270 - 270. [Abstract] [PDF]
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 U. Stolzel, E. Kostler, D. Schuppan, M. Richter, U. Wollina, M. O. Doss, C. Wittekind, and A. Tannapfel Hemochromatosis (HFE) Gene Mutations and Response to Chloroquine in Porphyria Cutanea Tarda Arch Dermatol, March 1, 2003; 139(3): 309 - 313. [Abstract] [Full Text] [PDF]
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 E. Beutler, A. V. Hoffbrand, and J. D. Cook Iron Deficiency and Overload Hematology, January 1, 2003; 2003(1): 40 - 61. [Abstract] [Full Text] [PDF]
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C. Ged, D. Ozalla, C. Herrero, M. Lecha, M. Mendez, H. de Verneuil, and J. M. Mascaro Description of a New Mutation in Hepatoerythropoietic Porphyria and Prenatal Exclusion of a Homozygous Fetus Arch Dermatol, July 1, 2002; 138(7): 957 - 960. [Abstract] [Full Text] [PDF]
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 S. W. Robinson, B. Clothier, R. A. Akhtar, A. L. Yang, I. Latour, C. Van Ijperen, M. F. W. Festing, and A. G. Smith Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of `Dioxin' with Iron Overload in Mice Mol. Pharmacol., March 1, 2002; 61(3): 674 - 681. [Abstract] [Full Text] [PDF]
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J. D. Phillips, T. L. Parker, H. L. Schubert, F. G. Whitby, C. P. Hill, and J. P. Kushner Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase Blood, December 1, 2001; 98(12): 3179 - 3185. [Abstract] [Full Text] [PDF]
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 C. N. Roy and N. C. Andrews Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers Hum. Mol. Genet., October 1, 2001; 10(20): 2181 - 2186. [Abstract] [Full Text] [PDF]
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G. Le Gac, C. Mura, and C. Ferec Complete Scanning of the Hereditary Hemochromatosis Gene (HFE) by Use of Denaturing HPLC Clin. Chem., September 1, 2001; 47(9): 1633 - 1640. [Abstract] [Full Text] [PDF]
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J. D. Phillips, L. K. Jackson, M. Bunting, M. R. Franklin, K. R. Thomas, J. E. Levy, N. C. Andrews, and J. P. Kushner A mouse model of familial porphyria cutanea tarda PNAS, December 22, 2000; (2000) 11481398. [Abstract] [Full Text]
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 Z. J. Bulaj, R. S. Ajioka, J. D. Phillips, B. A. LaSalle, L. B. Jorde, L. M. Griffen, C. Q. Edwards, and J. P. Kushner Disease-Related Conditions in Relatives of Patients with Hemochromatosis N. Engl. J. Med., November 23, 2000; 343(21): 1529 - 1535. [Abstract] [Full Text] [PDF]
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J. D. Phillips, L. K. Jackson, M. Bunting, M. R. Franklin, K. R. Thomas, J. E. Levy, N. C. Andrews, and J. P. Kushner A mouse model of familial porphyria cutanea tarda PNAS, January 2, 2001; 98(1): 259 - 264. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
interferon (IFN-