Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda

Porphyria cutanea tarda is a skin disease caused by photosensitization by porphyrins whose accumulation is caused by deficiency of hepatic uroporphyrin- ogen decarboxylase activity. Mutations in the uroporphyrinogen decarboxylase gene are present in the low-penetrant, autosomal dominant familial form but not in the commoner sporadic form of porphyria cutanea tarda. We have investigated the relationship between age of onset of skin lesions and mutations (C282Y, H63D) in the hemochromatosis gene in familial (19 patients) and sporadic porphyria cutanea tarda (65 patients). Familial porphyria cutanea tarda was identified by mutational analysis of the uroporphyrinogen decarboxylase gene. Five previously described and eight novel mutations (A80S, R144P, L216Q, E218K, L282R, G303S, 402-403delGT, IVS2 + 2 delTAA) were identified. Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphyria cutanea tarda, the effect being more marked in familial porphyria cutanea tarda where anticipation was demonstrated in family studies. Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is an important susceptibility factor in both types but suggested that heterozygosity for this mutation has much less effect on the development of the disease.     

Familial porphyria cutanea tarda with normal erythrocytic urodecarboxylase: an exception to the rule?

The possibility that the differentiation between sporadic and familial porphyria cutanea tarda cannot always be made on the basis of the measurement of the erythrocytic uroporphyrinogen decarboxylase activity has been examined. Two cases of porphyria cutanea tarda, with a normal erythrocytic enzyme activity in a father and son, are described. The authors exclude that these are 2 cases of sporadic or toxic porphyria cutanea tarda within the same family. These 2 cases provide additional evidence for the existence of a form of familial porphyria cutanea tarda in which erythrocytic uroporphyrinogen decarboxylase activity is normal.     

Porphyria cutanea tarda in south-east New South Wales

Thirteen patients with porphyria cutanea tarda diagnosed between 1994 and 2000 were reviewed to evaluate the precipitating factors and associations of porphyria cutanea tarda in a regional area of coastal and rural NSW. The majority had more than one precipitating factor, with excess alcohol intake, mutations in the haemochromatosis gene, chronic hepatitis C infection and oestrogen therapy being the most common. Antibodies to the hepatitis C virus were detected in 25% and these patients presented at a younger age. Of the patients tested for the two known haemochromatosis gene mutations, six (46%) had at least one copy of the C282Y mutation. Two (15%) patients were homozygous for the C282Y mutation and two (15%) were compound heterozygous for the C282Y and H63D mutations. All patients responded to venesection, which is the treatment of choice for the majority of patients with porphyria cutanea tarda.     

Role of the hemochromatosis gene in prophyria cutanea tarda. Prospective study of 56 cases]

BACKGROUND: The cause of iron overload in prophyria cutanea tada is unknown. The aim of this work was to determine the frequency of the hemochromatosis gene (HFE) in 56 patients with porphyria cutanea tarda. We analyzed the relationship between HFE mutations and biochemical abnormalities in porphyria cutanea tarda and the interaction with other triggering factors of porphyria cutanea tarda (alcohol abuse, hepatitis C, drugs).PATIENTS AND METHODS: Hepatitis C, alcohol abuse, drug intake and HFE mutations were determined in 56 patients with porphyria cutanea tarda (44 men and 12 women). Iron status was determined from transferrin saturation, serum iron, and serum ferritin. Liver metabolism was determined from liver chemistries: alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase.RESULTS: Thirty-nine patients (69.4 p. 100) carried HFE mutations, 18 (32.1 p. 100) were H63D heterozygous, 4 (7.1 p. 100) were H63D homozygous, 9 (16 p. 100) C282Y heterozygous, 8 (14.2 p. 100) compound C282Y/H63D heterozygous and none were C282Y homozygous. Comparison between porphyria cutanea tarda with and without mutations showed that compound C282Y/H63D heterozygous status was significantly linked to iron overload: transferrin saturation=0.61 vs 0.39 (p=0.0001) and serum iron=32.9 vs 22.4 (p=0.0046). H63D homozygous status was linked to iron overload but non-significantly: transferrin sturatin=0.53 vs 0.39 (p=0.06). The class with high iron overload (transferrin saturation > 0.45) was not linked with triggering factors of porphyria cutanea tarda. Hepatatic cytolysis was linked to alcohol abuse and hepatitis C but not to HFE mutations.DISCUSSION: The frequencies of HFE mutations in Lyons France are halfway between Anglo-Saxon and Italian papers, highlighting the Celtic origin of C282Y mutation. Compound heterozygous and to a lesser degree H63D homozygous status explained the highest iron overload in our patients. This favors clinical expression of porphyria cutanea tarda. This iron overload due to HFE mutations is a new triggering factor of porphyria cutanea tarda independent of classical triggering factors: mutation of the erythrocytic uroporpyrinogen decarbocylase gene, alcohol abuse, hepatitis C, and drugs.     

Porphyria cutanea tarda

Porphyria cutanea tarda (PCT) is a metabolic disorder of haem biosynthesis caused by decreased activity of uroporphyrinogen decarboxylase. Porphyria cutanea tarda is manifest by fragility, erosions, bullae, milia and scars on sun-exposed skin. Excess porphyrins in the skin interact with light of approximately 400 nm-wavelength radiant energy, forming reactive oxygen species. Porphyria cutanea tarda is categorized as familial, acquired or toxic. Factors that may induce clinical expression of PCT in susceptible individuals include alcohol, oestrogen, iron, polyhalogenated compounds and viral infections. Porphyria cutanea tarda is associated with an increased incidence of the haemochromatosis gene. Treatments for PCT include withdrawal of aggravating factors, phlebotomy and oral antimalarial medications.     

HFE mutations and transferrin receptor polymorphism analysis in porphyria cutanea tarda: a prospective study of 36 cases from southern France

BACKGROUND: Porphyria cutanea tarda (PCT) is associated in most cases with iron overload, which may participate in decreased activity of uroporphyrinogen decarboxylase in the liver. The aetiology of this iron overload remains unknown; however, it has been demonstrated that mutations of HFE, the genetic haemochromatosis gene, might be present in a significant proportion of Anglo-Saxon and Italian patients. Furthermore, transferrin receptor polymorphism may influence the affinity of this receptor to its ligand with a subsequent increase of cellular iron absorption and storage. OBJECTIVES: To evaluate the incidence and spectrum of HFE mutations and the relative frequency of the two main alleles of transferrin receptor in patients with PCT originating from southern France, and to evaluate the relationship of these genetic data with iron status, and with hepatitis B and C and human immunodeficiency virus (HIV) infections. METHODS: Thirty-six consecutive patients with either sporadic or familial PCT were prospectively included between 1997 and 2000. Search for the presence of the three main mutations of the HFE gene and identification of the transferrin receptor alleles were performed using polymerase chain reaction followed by enzymatic digestion. Iron parameters and viral status for hepatitis B and C viruses and HIV were determined. RESULTS: Seven patients (19%) showed heterozygous C282Y mutation, but no C282Y homozygote was present; five patients (14%) carried homozygous H63D mutation, while eight (22%) were heterozygous for this mutation. One patient was heterozygous for the S65C mutation (3%). Iron parameters demonstrated overload in all patients, without a clear difference between patients with and without deleterious mutations of the HFE gene. Infection by hepatitis C virus was documented in 20 patients (56%), and was significantly less frequent in patients with deleterious HFE mutations. The profile of transferrin receptor alleles in PCT patients did not show significant variation compared with the general population. CONCLUSIONS: This study confirms the high frequency of HFE mutations in patients with PCT and supports the hypothesis that HFE gene abnormalities might play a significant part in the PCT pathomechanism, probably through iron overload; by contrast, transferrin receptor polymorphisms do not appear to play a significant part in iron overload in PCT.     

Measurement of liver iron content by magnetic resonance imaging in 20 patients with overt porphyria cutanea tarda before phlebotomy therapy: a prospective study

Liver iron content was evaluated by a magnetic resonance imaging-based method in 20 consecutive patients with either sporadic or familial porphyria cutanea tarda. Serum ferritin, hepatitis C infection and the presence of the 2 main mutations of the hemochromatosis gene were also investigated. All patients showed good clinical response to phlebotomy. Initial liver iron content was normal (< 40 micromol/g) in 9 cases, slightly increased (40-59 micromol/g) in 3 cases, moderately increased (60-99 micromol/g) in 6 cases or markedly increased (100-199 micromol/g) in 2 cases). The ferritin level was raised (> 400 ng/ml) in 14/20 patients and there was no obvious relationship with liver iron. Increased liver iron content was observed more frequently in patients with hemochromatosis mutation and less frequent in those with hepatitis C infection. Clinical response to phlebotomies was slightly better in patients with increased liver iron content even slightly, but patients with normal liver iron content also responded well, which suggests that iron depletion is an outstanding treatment independent of liver iron content. This study shows that increased liver iron content is not a constant finding in patients with porphyria cutanea tarda, especially in women, and that it is not a prerequisite for the efficiency of phlebotomy.     

Porphyria cutanea tarda and peptic ulcer

A high incidence of peptic ulcer was found in a retrospective study of 199 Bulgarians with porphyria cutanea tarda. Ulcers were found in 35 patients (17.59%), while its incidence in Bulgaria varies between 2.52 and 3.7%. The site of the ulcer was duodenal in 29 porphyriacs, gastric in three, both duodenal and gastric in two and pyloric in one. The pattern of localization was similar to that seen in the general population. Peptic ulcers became symptomatic before the appearance of porphyria in 30 cases. Six (17.1%) of the patients had perforations, while the frequency of this complication in the general population was 1.7-8.5%. Two porphyriacs with perforations died of peritonitis. Ulcers were found in 21 (24.4%) of 86 patients with normal activity of erythrocyte uroporphyrinogen decarboxylase, i.e. they had sporadic (acquired) porphyria cutanea tarda. Two (10%) of 20 patients suffering from the familial form of the disease (with low erythrocyte uroporphyrinogen decarboxylase activity) had ulcers. The examination of 105 unselected porphyriacs showed a significantly higher incidence of blood group B in comparison with the general population (23.8% vs. 16.6%). The association between the porphyriacs with ulcers and blood group B (8 of 21 examined persons) and the rare occurrence of group O (only 4 of 21) was unexpected. An association between porphyria and some of the haptoglobin types could not be established in 98 unselected patients (including those with and without ulcer). More studies are needed to substantiate the validity of blood groups and uroporphyrinogen decarboxylase as genetic markers for porphyria cutanea tarda combined with peptic ulcer. Porphyria cutanea tarda (PCT) is the commonest human porphyria in most countries of the world. It is characterized by photosensitivity, mild to moderate hepatic siderosis and marked elevation of the highly carboxylated porphyrins in plasma and urine. A significantly higher incidence of peptic ulcer (PU) was reported in PCT patients in Spain in comparison with the general population.¹ The reason for this is unknown. The liver damage and the alcohol consumption in most PCT patients could only partially explain such a high frequency. In both diseases, the aetiological role of hereditary and genetic factors have been considered. It is known that in patients with duodenal ulcer, blood group O is particularly common.² Two forms of PCT exist. In the familial type a decreased activity of the enzyme, uroporphyrinogen decarboxylase (Uro D) is found in erythrocytes. In sporadic (acquired) PCT the enzyme activity in erythrocytes is normal. However, some hereditary predisposition in the sporadic form cannot be excluded.³ This makes an investigation of some genetic markers in PCT a reasonable goal. The HLA system has been already studied in this disease, but the results do not provide a clear-cut conclusion.^4–6 We were not able to find any data on two other routinely determined genetic markers—the blood groups and haptoglobin types. As an increased association between PCT and PU could be expected anyway, and not only in Spain, and as it seems appropriate to determine the blood groups and haptoglobin types in PCT, we undertook the present study. Its aim was to examine (i) the incidence of PU among patients with familial and sporadic PCT in Bulgaria and (ii) the distribution of blood group and haptoglobin types in PCT patients as a whole and in the porphyriacs with and without PU.     

Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients

BACKGROUND

Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil.

OBJECTIVES

Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations.

METHODS

An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR.

RESULTS

Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors.

CONCLUSIONS

Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients     

PORPHYRIA CUTANEA TARDA IN A SEVEN YEAR OLD CHILD

A case of porphyria cutanea tarda in a seven year old child is reported. This was demonstrated to be a familial type by uroporphyrinogen decarboxylase estimations in the patient and her family. Treatment of the patient with chloroquin is described.     

Update on enzyme and molecular defects in porphyria

Each porphyria results from decreased activity of one of the enzymes of haem biosynthesis. The molecular basis of enzyme deficiencies in acute intermittent porphyria (AIP), variegate porphyria (VP) and congenital erythropoietic porphyria (CEP) is outlined. All three conditions show extensive allelic heterogeneity. In the autosomal dominant disorders, AIP and VP, no genotype/phenotype correlations have been demonstrated, and the explanation for their low clinical penetrance remains uncertain. In AIP and VP, mutational analysis is superior to biochemical methods for screening families for latent porphyria. In the autosomal recessive condition, CEP, there is some genotype/phenotype correlation — one common mutation (C73R) being associated with severe disease in homozygotes. Porphyria cutanea tarda (PCT) is not a simple monogenic disorder. Patients appear to have an inherited susceptibility to inactivation of hepatic uroporphyrinogen decarboxylase (UROD) as part of a response to hepatocyte injury by alcohol, HCV and other agents. Inherited factors that, in combination, may predispose to PCT include mutations in the UROD gene, present in about 20% of patients, and the C282Y mutation in the haemochromatosis (HFE) gene.     

The genetic basis of porphyria cutanea tarda

In order to confirm the genetic character of porphyria cutanea tarda (PCT), the quantitative and qualitative porphyrin excretion from 56 unrelated PCT patients and 259 relatives was analyzed by a sensitive fluorimetric thin-layer chromatographic technique. Porphyrin excretion abnormalities were observed in 111 (35.24%) of the 315 subjects studied. Of the 259 relatives, 55 (21.24%) suffered from manifest (24 cases) or subclinical (31 cases) PCT. The relatives from the older generation or a generation similar to the propositi were more frequently affected than those from a younger generation. A clear family incidence was observed in 32 families, while PCT was apparently limited to the propositi in the remaining 24. It is discussed whether these latter families correspond to the so-called "sporadic" type of PCT or include porphyric gene carriers lacking biochemical expression of the disease. While the measurements of the activity of the defective enzyme (uroporphyrinogen decarboxylase) for the genetic research of PCT turned out to be impracticable in hepatic tissue and contradictory in erythrocytes, our study confirms that the familial character of this disease may be revealed by the chromatographic analysis of the porphyrin excretion pattern.     

Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern

Hepatoerythropoietic porphyria (HEP) is an uncommon inherited cutaneous porphyria, related to porphyria cutanea tarda, that results from severe uroporphyrinogen decarboxylase (UROD) deficiency. It is characterized clinically by the onset in early childhood of severe lesions on sun-exposed skin. We describe a man aged 38 years with an unusually mild form of the disease that started in his early teens. Our data confirm that homozygosity for the F46L mutation in the UROD gene causes a mild form of HEP and show that this genotype may be associated with a unique urinary porphyrin excretion pattern in which pentacarboxylic porphyrin predominates.     

The management of porphyria cutanea tarda

Porphyria cutanea tarda (PCT), the commonest of all porphyrias, is usually characterized by blisters and fragility of skin in light-exposed areas. It can be clinically indistinguishable from other disorders including variegate porphyria and the diagnosis can only be made by rigorous biochemical analysis. PCT does not cause acute attacks of porphyria. It is usually an acquired condition caused by inhibition of the uroporphyrinogen decarboxylase enzyme in the liver. Hereditary haemochromatosis, hepatitis C virus infection, alcohol, oestrogens and a family history of PCT are the major risk factors for the condition and should be searched for specifically in all patients. Liver disease, including hepatocellular carcinoma, is common in patients with PCT, and should be investigated for at presentation by means of a liver biopsy where possible. Patients with severe hepatic pathology or longstanding untreated PCT need to be monitored for the development of hepatocellular carcinoma in the long term. Low dose twice weekly chloroquine is the mainstay of treatment, but venesection should be used in patients with severe iron overload or hepatitis C-related liver disease. Subsequently, long-term follow-up is needed in all patients to monitor for relapse.     

Human immunodeficiency virus infection and porphyria cutanea tarda

A recent report documents three homosexual men with porphyria cutanea tarda associated with acquired immune deficiency syndrome (AIDS). We report two brothers with hemophilia and human immunodeficiency virus (HIV) exposure who developed porphyria cutanea tarda. These brothers are heterosexual, have familial porphyria cutanea tarda, and developed overt familial porphyria cutanea tarda in their early twenties. One brother's symptoms were provoked by attending an ultraviolet A suntanning parlor. Our two patients, unlike the previously reported three patients, have not developed AIDS, though one patient has evidence of defective cell-mediated immunity. Three of the five cases of porphyria cutanea tarda associated with HIV infection involved familial porphyria cutanea tarda. It now may be advisable to order HIV serology tests in patients who have porphyria cutanea tarda. We recommend that HIV-positive individuals avoid ultraviolet A radiation because of its immunosuppressive effects in persons already at risk of immunosuppression. Such exposure is further contraindicated in those individuals with porphyria cutanea tarda.     

Familial porphyria cutanea tarda

The results of erythrocyte uroporphyrinogen decarboxylase estimations of members of the family of a child with porphyria cutanea tarda are reported.     

Manifestation of familial porphyria cutanea tarda after childbirth

We report the case of a woman with hereditary porphyria cutanea tarda which manifested 3 weeks after she gave birth to her second child. The mother of the patient had also been diagnosed and treated for porphyria cutanea tarda. Reduced red cell uroporphyrinogen decarboxylase activity was found in the patient, the new-born child and the patient's mother. Normal enzyme activity was found in the patient's first child.     

Recovery from porphyria cutanea tarda with no specific therapy other than avoidance of hepatic toxins

Little is known of the natural progression of untreated porphyria cutanea tarda. We report sixteen cases (fourteen sporadic and two familial) in which the cutaneous and biochemical abnormalities improved without any specific therapy other than the avoidance of hepatic toxins.     

Erythrocyte uroporphyrinogen decarboxylase activity in 80 unrelated patients with porphyria cutanea tarda

To estimate the prevalence of the subgroups of porphyria cutanea tarda (PCT), erythrocyte uroporphyrinogen decarboxylase (UD) activity was measured in 80 unrelated patients with PCT, and in 45 of their relatives by using pentacarboxyl-porphyrinogen III as substrate. The subgroups were differentiated by analysis of the urinary porphyrins of the patients and 119 of their relatives. Of the patients, 77.5% were found to be suffering from the sporadic form of PCT (type I PCT), and 22.5% from the familial form (type II PCT). Every patient with PCT had previously been affected by alcohol, oestrogen or some other liver-damaging factor. The relative frequency of familial PCT was higher in females (nine of 15) than in males (nine of 65), which suggests that inheritance of the gene for type II PCT may predispose to oestrogen-precipitated PCT. The onset of type II PCT occurred at a lower age than that of type I (42.6 vs. 47.0 years). The findings suggest an increased risk of precipitating factors in carriers of an inherited UD deficiency.