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PubMed2002

The decrease in uroporphyrinogen decarboxylase activity induced by ethanol predisposes rats to the development of porphyria and accelerates xenobiotic-triggered porphyria, regardless of hepatic damage.

We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.

Animals↗
PubMed1986

Porphyria cutanea tarda. Diagnosis, management, and differentiation from other hepatic porphyrias.

Porphyria cutanea tarda is a photocutaneous syndrome characterized clinically by cutaneous fragility, bullae, hypertrichosis, pigmentary changes, and sclerodermoid plaques and characterized biochemically by hepatic overproduction and storage of excessive amounts of porphyrins. Porphyria cutanea tarda, the most common disorder of porphyrin metabolism, must be differentiated from variegate porphyria, hereditary coproporphyria, bullous dermatosis of hemodialysis, and drug-related pseudoporphyria.

Biopsy↗
PubMed1982

Severe cutaneous porphyria in a 12-year-old boy: hepatoerythropoietic or symptomatic porphyria?

Deforming cutaneous porphyria developed in a 12-year-old boy; the severity of his skin disease resolved spontaneously as he grew older. The clinical and biochemical aspects of this case clearly fit the descriptions in the medical literature of both hepatoerythropoietic porphyria (HEP) and infantile symptomatic porphyria (SP). Further porphyrin analyses indicated that our patient suffered from infantile SP. The lack of unquestionably unique features diagnostic for HEP raises strong doubts that it exists as a separate disease entity substantially different from infantile SP.

Child↗
PubMed1993

[Activity of delta-aminolaevulinic acid (ALAD) in erythrocytes of patients with chronic hepatic porphyria (porphyria cutanea tarda)].

Erythrocyte delta-aminolaevulinic acid dehydratase (ALAD) activity was estimated in chronic hepatic porphyria, correlated with some tests of liver function and compared with enzyme activity in chronic liver diseases. 24 patients with chronic hepatic porphyria, 22--with chronic liver diseases and 30--controls were examined. European standardised method for the determination of ALAD activity blood was used. The significantly lowest activity was found in porphyric patients even after reactivation with zinc and dithiothreitol. There was no significant difference between ALAD activity in chronic liver diseases and controls. These results and lack of correlation between enzyme activity and liver function tests suggest that ALAD activity is decreased in chronic hepatic porphyria and is independent of liver damage.

Adult↗
PubMed1998

[Porphyria cutanea tarda is the most common type of porphyria. Medical control is a team work].

Porphyria cutanea tarda (PCT) is probably the most common of the porphyrias. The development of skin fragility and blisters are the symptoms that generally bring the patient to the notice of the dermatologist. During the past decade the disease has been recognised as being of heterogeneous aetiology, and a pathogenetic classification has been proposed. The significance of subtyping for the choice of management strategy is currently appreciated, as is the need of close monitoring owing to the risk of the common PCT-associated liver conditions. Preferably the PCT patient should be managed by a dermatologist and a hepatologist working in concert and supported by a specialised porphyria laboratory. The use of a structured management protocol should be considered.

Diagnosis, Differential↗
PubMed1999

[Acute intermittent porphyria and simulated acute porphyria: case reports].

The authors present according to a case of acute intermittent porphyria, diagnostic and therapeutical problems, which are met by physicians in a regional hospital (case 1). Simultaneously the authors present a case of woman with opiate depends syndrome, who has simulated attacks of acute porphyria for the last few years in order to obtain narcotic drugs (case 2).

Adult↗
PubMed1992

[Hereditary porphyria and acquired porphyria in the child. Five case reports].

Two cases of inherited porphyrinopathies and three cases of acquired porphyrinopathies are described. The two inherited cases were cutaneous porphyrias with 50% reduction of enzyme activities: one case of erythropoietic protoporphyria in a 2 year-old male and one case of familial cutaneous porphyria in a 7 year-old boy. The three cases of acquired porphyrinopathy included one case of lead poisoning in a 3 year-old boy and 2 cases of hereditary tyrosinemia in 1 and 2 year-old infants. Urinary and erythrocytes porphyrins and precursors (5 aminolevulinic acid and porphobilinogen) levels were used for diagnosis and to follow the response to treatment.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.

BACKGROUND: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity,is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). OBJECTIVE: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. DESIGN: Clinical, imaging, and genotype/phenotype studies were performed. RESULTS: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1% of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2% of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. CONCLUSIONS: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.

Acute Disease↗
PubMed2001

Identification of the first variegate porphyria mutation in an indigenous black South African and further evidence for heterogeneity in variegate porphyria.

Variegate porphyria is an autosomal dominant disorder of haem metabolism resulting from reduced levels of the penultimate enzyme in the pathway, protoporphyrinogen oxidase. Here we investigate the molecular basis of variegate porphyria in four non-R59W South African families. We report the identification of the first mutation in the protoporphyrinogen oxidase gene in a black South African individual (V290M). In addition, we document three further mutations, a missense mutation (L15F), a deletion followed by a substitution [c769delG;770T > A], and a nonsense mutation (Q375X), in individuals of European or mixed ancestry. Our data provide further evidence of genetic heterogeneity in South Africa.

Adult↗
PubMed1988

Prevalence of the 281 (Gly----Glu) mutation in hepatoerythropoietic porphyria and porphyria cutanea tarda.

The prevalence of the 281 (Gly----Glu) mutation in hepatoerythropoietic porphyria (HEP) was investigated by the use of hybridization with a synthetic oligonucleotide probe. The mutation was found in HEP-affected members of two unrelated families from Spain, but was absent in two other patients from Italy and Portugal who also had HEP. Moreover, this mutation was not detected in 13 unrelated cases of familial (type II) porphyria cutanea tarda.

Carboxy-Lyases↗
PubMed1972

Identification of a group of tetracarboxylate porphyrins, containing one acetate and three propionate -substituents, in faeces from patients with symptomatic cutaneous hepatic porphyria and from rats with porphyria due to hexachlorobenzene.

1. Three tetracarboxylate porphyrins, apart from coproporphyrin, were isolated from the faeces of patients with symptomatic cutaneous hepatic porphyria and of rats with porphyria caused by hexachlorobenzene poisoning. The porphyrins were not present in the urine of the porphyric rats or in the faeces of control rats. 2. Two of the porphyrins were identified as tris-(2-carboxyethyl)-carboxymethyl ethyl trimethyl porphin (isocoproporphyrin) and tris-(2-carboxyethyl)-carboxymethyl trimethyl porphin (de-ethyliso-coproporphyrin). 3. The third porphyrin, previously reported to be an analogue of coproporphyrin in which one propionate group is replaced by an alpha- or beta-hydroxypropionate group, was shown to be tris-(2-carboxyethyl)-carboxymethyl-(1-hydroxyethyl)-trimethyl porphin (hydroxyisocoproporphyrin). 4. The order of beta-substituents around the porphin ring could not be determined for any of the compounds. 5. Evidence for the existence of a fourth porphyrin, tris-(2-carboxyethyl)-carboxymethyl trimethyl vinyl porphin (dehydroisocoproporphyrin), a postulated precursor of the others, is described. 6. It is suggested that dehydroisocoproporphyrinogen is produced by decarboxylation-dehydrogenation of one of the propionate groups of pentacarboxylate porphyrinogen III.

Acetates↗
PubMed1975

[Hepato-erythrocytic porphyria. A new type of porphyria].

A case of porphyria with symptomatology beginning in early infancy with peculiar biochemical features is described. There were crops of blisters, an extraordinary hypertrichosis and scarring of the exposed skin. The porphyrin examination showed an abnormal excretion pattern of urinary porphyrins with large amounts of 5-COOH carboxyle porphyrins and the protoporphyrin level of the red cells was raised. There was fluorescence of the erythrocytes and erythroblasts. The porphyrin excretion pattern of the stools was similar to those of the PCT. This case is closely similar to another published by the authors in 1969 and to 2 published by Schneider and Simon. The authors consider that could represent a new type of porphyria.

Child↗
PubMed1986

Porphyria turcica: hexachlorobenzene-induced porphyria.

It has been estimated that during 1955-1959 in southeastern Turkey, approximately 4000 people developed porphyria due to ingestion of hexachlorobenzene (HCB), a fungicide added to wheat seedlings. Patients subsequently developed bullae on sun-exposed areas, hyperpigmentation, hirsutism, weakness and porphyrinuria. Children born to mothers who had ingested the grain were exposed to HCB in maternal milk and transplacentally, resulting in the death of children under the age of two. In this follow-up study, 204 patients with a past history of HCB-induced porphyria were re-evaluated. There were 132 males and 72 females, with an average age of 32.1 years, an average age of onset of 7.1 years and a duration of 2.4 years. The clinical features of the 204 patients were: scarring of the face and hands in 86.7%, hyperpigmentation in 71.1%, hirsutism in 47.1%, pinched facies in 41.2%, fragile skin in 37.7%, painless arthritis in 66.6%, small hands in 64.2%, an enlarged liver in 4.4% and an enlarged thyroid in 37.3%; most patients also showed neurological symptoms. Urine and stool porphyrin levels were determined in all patients. Seventeen showed elevated levels of one of the porphyrins and eight were considered still porphyric after 25-30 years. A total of 56 specimens of human milk obtained from porphyric mothers were analysed for HCB. The average value was 0.51 ppm compared with 0.07 in controls. After HCB ingestion, abnormal porphyrin metabolism, dermatological, orthopaedic and neurological findings, and HCB residues in the milk of porphyric patients have been shown to persist at least for 25-30 years.

Adult↗
PubMed1986

Depletion of histidine and tryptophan serum levels in porphyria cutanea tarda and congenital erythropoietic porphyria patients after irradiation with visible light.

We have studied the photosensitized oxidation, via singlet oxygen production, of histidine (His) and tryptophan (Trp) in the serum of porphyria patients and in the serum of healthy volunteers before or after addition of hematoporphyrin. It was observed that free plasma His and Trp are good probes of singlet oxygen production in the blood under visible light irradiation. However, Trp, which is mostly bound to serum albumin, is much less susceptible to photooxidation than His, which remains free in the plasma. These results must not be ignored in systemic effects of porphyrias and in photochemotherapy with hematoporphyrin derivatives.

Blood↗
PubMed1984

Enzymatic and immunological studies of uroporphyrinogen decarboxylase in familial porphyria cutanea tarda and hepatoerythropoietic porphyria.

Uroporphyrinogen decarboxylase activity was measured in hemoglobin-free lysates from two patients with hepatoerythropoietic porphyria (HEP) and from 12 unrelated patients with familial porphyria cutanea tarda (PCT). In HEP patients, enzyme activities were 5% of normal, and familial studies clearly confirmed that patients with HEP are cases of homozygous PCT. Immunoreactive uroporphyrinogen decarboxylase was measured by developing a direct and noncompetitive enzyme immunoassay (EIA). For the 12 familial PCT patients, we found an immunoreactive protein decreased (51%) to the same extent as the catalytic activity (48%) [cross-reactive immunological material ( CRIM ) negative]. The children from the HEP family were also CRIM negative, contrasting with another HEP family previously described as CRIM positive; our data support the hypothesis of a heterogeneity in familial uroporphyrinogen decarboxylase deficiency.

Carboxy-Lyases↗
PubMed1993

Total intravenous anesthesia in South-African genetic porphyria (variegate porphyria).

The authors report the case of a female patient with South-African genetic porphyria who had to undergo hepatic tumorectomy under general anesthesia. The choice for propofol as the induction and maintenance agent using a balanced anesthetic technique led to a significant rise in urinary excretion of porphyrins without associated clinical manifestations. A short review of the literature on physiopathology of porphyrias and medicinal agents, susceptible to induce acute porphyric crisis follows. The authors conclude that the innocuity of propofol as induction and maintaining agent in the porphyric patient cannot be yet established without further studies.

Adult↗
PubMed1998

Cytoplasmic liver cell inclusions--a typical feature of porphyria cutanea tarda--are absent in porphyria-related hepatic neoplasias.

Crystalline cytoplasmic needle-shaped inclusions in hepatocytes are considered to represent a specific morphological feature of porphyria cutanea tarda (PCT) and experimental PCT-like porphyrias. The cytoplasmic inclusions, however, are absent in hyperplastic hepatic nodules and hepatocellular carcinomas arising in the course of these conditions. It is assumed that porphyrins and related substances accumulated in hyperplastic and neoplastic hepatic lesions differ from those found in non-neoplastic liver tissue: the highly carboxylated porphyrins are stored in both sites, the crystal-forming substance only in non-proliferating liver tissue.

Animals↗
PubMed1972

Studies in porphyria. I. A defect in the reductive transformation of natural steroid hormones in the hereditary liver disease, acute intermittent porphyria.

A variety of 5beta steroid metabolites derived from hormones natural to man are potent inducers experimentally of delta-aminolevulinate synthetase, the rate-limiting enzyme in porphyrin-heme formation. This mitochondrial enzyme is found at high levels of activity in the livers of patients with the genetic disease, acute intermittent porphyria (AIP). In this study the metabolism of (14)C-labeled testosterone was examined in AIP patients to determine whether there was a disproportionate conversion of the hormone to its 5beta, compared to its 5alpha metabolite. The results indicate that AIP subjects do generate a substantially greater than normal fraction of 5beta metabolite from this steroid; the excessive degree of ring A reduction of testosterone taking place via the 5beta pathway in the porphyric patients averages 350% greater than in the nonporphyric subjects. In one asymptomatic AIP patient the disproportionate generation of 5beta metabolite from the hormone reached a level 10 times the normal mean. Studies with a second (14)C-labeled hormone, dehydroisoandrosterone, whose metabolism in man resembles that of testosterone, confirmed the derangement in reductive transformation of steroids found in the individuals carrying the genetic lesion of AIP. These findings define a new endocrine abnormality in AIP patients and raise the possibility that endogenously derived 5beta steroids may contribute by an induction mechanism to the increased levels of hepatic delta-aminolevulinate synthetase activity found in AIP patients.

5-Aminolevulinate Synthetase↗