Childhood-onset mild cutaneous porphyria with compound heterozygotic mutations in the uroporphyrinogen decarboxylase gene.

Three children (two boys and one girl) from the same family presented with photosensitivity, hyperpigmentation, hypertrichosis, mild skin fragility, blistering and scarring in childhood. On examination, the cutaneous lesions were found to have improved since their previous examinations. Laboratory tests showed raised plasma and urine carboxyporphyrins and decreased uroporphyrinogen decarboxylase enzyme activity in red blood cells. Triggering factors for porphyria were not detected except for a hepatitis C virus infection in the younger boy. The girl's clinical symptoms recurred in late adolescence, after iron and oestrogen treatments. Mutation analysis of the UROD gene detected two missense mutations, 19 A-->G M1V (novel) and 703C-->T P235S (previously reported), in an uncommon compound heterozygous manner in the three siblings.

[Are the hemochromatosis (HFE) gene mutation and hepatitis C virus (HCV) infection risk factors for porphyria cutanea tarda?]. / Porphyria cutanea tarda: kockázati tényezó-e a haemochromatosis gén (HFE)-mutáció és a hepatitis-C vírus (HCV)-infekció?

As it is not clear whether mutations in hemochromatosis gene (HFE) and hepatitis C virus (HCV) act independently in the pathogenesis of porphyria cutanea tarda (PCT), and prevalence of both risk factors reveals a great variety in different parts of the world, PCT patients from our Central East European country were investigated for this aspect. The occurrence of the C282Y and H63D mutations in HFE gene were determined in 19 PCT patients and compared with the reported control frequencies. Furthermore, the presence of HCV infection was determined and related to the patients' HFE status. The C282Y mutation was found in 3/19 cases (one patient was homozygous and two heterozygous), with an 10.5% allele frequency (vs. 3.8% control) (p < 0.05). Five patients were heterozygous for the H63D mutation, allele frequency 13.1%, which did not differ from the reported control prevalence of 12.3%. Six patients (31.7%) were HCV-RNA positive, out of the six one was heterozygous for H63D mutation and one was compound heterozygous. HCV infection and HFE C282Y mutations may probably be independent predisposing factors for development of PCT in Hungarian patients.

[Pathogenesis of porphyria cutanea tarda]. / A porphyria cutanea tarda patogenezise.

Porphyria cutanea tarda (PCT) results basically from decreased activity of uroporphyrinogen decarboxylase (UROD) in the liver. PCT is not a homogeneous disease; it can be either inherited or acquired. Not only alterations at the UROD gen locus but also other genetic factors outside the locus take part in the inactivation of UROD, that support polygenic inheritance of PCT. In every case, acquired factors take also part in development of the overt form of PCT. Iron has a key-role in the oxidative damages.

[Porphyria cutanea tarda in a long-term hemodialysis patient]. / Porphyria cutanea tarda bei einem Langzeithämodialysepatienten.

A 61 year old man developed bullous skin lesions typical for porphyria cutanea tarda (PCT) after being on maintenance hemodialysis for 3 years. The porphyrin level in the urine, plasma, erythrocytes and stool supported the diagnosis of porphyria cutanea tarda, a very rare disease in patients with chronic renal failure on hemodialysis. Therapeutic possibilities are reviewed.

Porphyria cutanea tarda and chronic lymphoid leukemia.

A case of a familial porphyria cutanea tarda (PCT-II) is reported in which the clinically overt form of PCT was provoked by factors relating to chronic lymphoid leukemia (CLL). Typical lesions of PCT developed on a 55-year-old woman after several blood transfusions and chlorambucil treatment. Besides these provoking factors, cytomegalovirus (CMV) infection was diagnosed. Erythrocyte uroporphyrinogen decarboxylase activity was about 50% of normal in the patient and in her two children. This case supports the suggestion that development of PCT in patients with hematological disorders is more than coincidental but may in fact be provoked by exogenous factors relating to the treatment of leukemia.

[Chronic hemodialysis-related porphyria/pseudoporphyria]. / Krónikus hemodialízissel kapcsolatos porphyria/pseudoporphyria.

In a considerable proportion of the patients with chronic renal failure, skin changes resembling porphyria cutanea tarda (PCT) develop some months to years after the onset of maintenance hemodialysis. This can be either real PCT, or secondary PCT, or PCT-like bullous dermatosis. In a minor proportion, real PCT can be diagnosed. In such cases, elevated total porphyrin levels with a predominance of uro- (I > III) and heptacarboxyl porphyrins (III > I) can be measured in the plasma (also in the urine, if not anuric), and fecal (perhaps urinary as well) isocoproporphyrin can be detected. The activity of the hepatic uroporphyrinogen decarboxylase (UD) is decreased in every type of PCT; in PCT-II, also that of the erythrocyte UD. In a higher proportion, secondary PCT (pseudo-PCT) develops. In this group, porphyrins are accumulated in the plasma due to the unsatisfactory renal function. Uro and hepta are the dominant fractions here as well, but alteration in the ratio of the uro isomers or the presence of isocoproporphyrin can not be expected. The UD activity is probably normal in every tissue. In 1% to 18% of the cases, PCT-like bullous dermatoses develop, but porphyrins are at normal levels in all compartments. The phototoxic agent here is other than porphyrin (e.g. nalidixic acid, furosemide, tetracycline, etc., or unknown). The authors review the knowledge on chronic hemodialysis-related PCT or the PCT-like bullous dermatoses: development of the above-mentioned conditions, clinical and morphological and biochemical features, difficulties in diagnosis, or the possibilities in therapy.

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.

Uroporphyrinogen decarboxylase deficiency in hepatoerythropoietic porphyria: further evidence for genetic heterogeneity.

Catalytic and immunoreactive erythrocyte uroporphyrinogen decarboxylase was measured in a woman with hepatoerythropoietic porphyria (HEP). The uroporphyrinogen decarboxylase activity was 24% of the mean value for normal controls and the concentration of the immunoreactive enzyme (106 ng/mgHb), measured with the rocket immunoelectrophoresis technique, did not differ from that of healthy controls. Consequently, catalytically inactive, cross-reactive immunological material (CRIM) was present, and the patient was CRIM-positive. This enzyme activity and immunoreactive enzyme concentration differs from those for previously known HEP patients, and represents a new mutation, evidence for heterogeneity in inherited uroporphyrinogen decarboxylase deficiency.

[Coexistence of porphyria cutanea tarda and lupus erythematosus]. / Uber das gemeinsame Vorkommen von Porphyria cutanea tarda und Lupus erythematodes.

We report on the appearance of porphyria cutanea tarda in a patient with systemic LE and in two patients with discoid LE. A review is given on the corresponding literature. It is suggested that both lupus erythematosus and porphyria cutanea tarda have multifactorial inheritance. The cause of coexistence can be common genes responsible for the genetic determination which also predispose to the occurrence of both diseases. The question of etiology still remains obscure. This coexistence raises, however, a more practical question as regards the therapeutic modalities for the two diseases.

[Sclerodermiform porphyria]. / Porphyria sclerodermiformis.

We give a retrospective survey on the clinical, histological, biochemical, and pathogenetical aspects of sclerodermiform changes rarely accompanying porphyria cutanea tarda (PCT). Sclerodermiform changes were seen in 12 patients (2% of all our PCT cases). In these patients, no correlation was found between the severity of the dermatological signs and symptoms and the degree of disturbance in the porphyrin metabolism. Biochemical remission was not accompanied by improvement of the sclerodermiform changes. The proportion of porphyrins with 4 or 5 COOH-groups was higher than that of PCT patients without sclerosis. The findings are consistent with the view that the development of sclerodermiform changes cannot be merely explained by phototoxic reactions, but the "dark-effect" of the porphyrins may also play an important role in the pathogenesis.

The role of possible membrane damage in porphyria cutanea tarda: a spin label study of rat liver cell membranes.

Two groups of rats were made porphyric by treatment for a shorter or a longer time with hexachlorobenzene (HCB); a third group was subjected to chronic treatment with ethanol; the fourth group comprised untreated, control animals. Suspensions were prepared of hepatocytes isolated from the livers of the animals in the individual groups, and in these systems the cell membranes were studied by spin labeling. In all three chronically treated groups, the order parameter calculated from the ESR spectra was significantly lower than that of the control group. The order parameters ofr the first three treated groups, however, did not differ significantly from one another. If either HCB or ethanol was incorporated into the isolated hepatocytes of the healthy control animals, the fluidity of the hepatocyte membranes increased. The order parameter decrease (compared to the control) for the hepatocyte membranes of the animals treated chronically with HCB or ethanol can be ascribed to the direct membrane-fluidizing effect of HCB or ethanol, and also to the altered lipid metabolism. With regard to the difference in the mechanisms of action of HCB and ethanol, on the basis of the experimentally proved membrane-damaging effect of the porphyrinogenic HCB it is probable that, besides other factors, the membrane damage may play an important role in the pathogenesis of porphyria cutanea tarda.

[The effect of some hexachlorobenzene catabolites on the porphyrin metabolism of rats (author's transl)]. / Die Wirkung einiger Hexachlorbenzol-Katabolite auf den Porphyrinstoffwechsel der Ratte.

In answering the question as to what role possible metabolites of hexachlorobenzene play in the procreation of toxic hexachlorobenzene porphyria in rats, both pure hexachlorobenzene and different mixtures were fed to them. In each case 20% of the hexachlorobenzene was replaced by pentachlorophenol, 1,2,4,5-tetrachlorobenzene, 1,2,3,4-tetrachlorobenzene, 1,2,3,5-tetrachlorobenzene, 2,3,4,5-tetrachlorophenol, 2,3,5,6-tetrachlorophenol, 2,3,4,6-tetrachlorophenol or chloranil. The determination of porphyrins at different intervals once the feeding had started did not give rise to an increase in the porphyria in any of these substances--which are seen as metabolites of hexachlorobenzene. Instead there was a distinct decrease in individual cases. From this the conclusion is drawn that none of the tested substances is the metabolite of hexachlorobenzene, which is in fact responsible for the hexachlorobenzene porphyria.

Effects of iron-loading and ethanol treatment on rat porphyrin metabolism.

Rats were fed for 50 weeks with a standard diet containing 5.9% ferric ammonium sulphate. Half of these animals drank normal water, and the other half water containing 5% ethanol (groups 1 and 2). Two other groups received normal food, but drank water containing 5 or 10% ethanol (groups 3 and 4) for 40 weeks. Histologic examinations revealed that the iron-loading resulted in only mild hepatic siderosis in groups 1 and 2, the degree of siderosis not differing appreciably in the two groups. The ethanol led to fatty degeneration too in the liver of animals in group 2. Both iron-loading and ethanol treatment, either separately or in combination, increased the porphyrin excretion, but the distribution of the various porphyrins in the urine and faeces showed merely the symptoms of an aspecific poisoning. A significantly elevated uroporphyrin excretion was not observed in any of the groups, and thus the results support the view that dietary iron-loading and ethanol consumption can not be regarded as direct aetiologic factors in the pathomechanism of porphyria cutanea tarda. At the same time, the results suggest that vitamin E therapy, frequently employed effectively in porphyria cutanea tarda, can not be considered a causal intervention as regards the mechanism of action.