Iron and porphyria cutanea tarda.

In order to evaluate the pathogenetic role of iron in Porphyria cutanea tarda (PCT), the metabolism of iron was studied in 440 patient with PCT and associated chronic liver disease (CLD) and in 91 nonporphyric CLD patients (used as a control group). The parameters considered were the following: serum iron, ferritin, Total Iron Binding Capacity (TIBC) and percent saturation of transferrin. The statistical analysis showed that the differences between the means, in the two groups, were not significant in any of the parameters examined. To investigate the possible relationships between iron metabolism and other chemico-clinical parameters concerning the porphyric disease, the associated hepatic disease and hemometry, we studied the correlations between iron parameters and total urinary and serum porphyrins, serum copper, serum albumin, hemoglobin, red blood cells, ALT, AST, CHE and GLDH. This investigation was only possible in the last 99 cases. In addition to the obvious correlations between the parameters concerning iron metabolism, the highly significant (p < 0.001) correlation between ferritin and enzyme activities which indicate cytolysis (ALT, AST, GLDH) is extremely interesting. The results seem to point to the tentative conclusion that the alterations of iron metabolism are more related to the hepatocellular necrosis than to the metabolism of porphyrins.

Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria.

A deficiency in uroporphyrinogen decarboxylase (UROD) enzyme activity, the fifth enzyme of the heme biosynthetic pathway, is found in patients with sporadic porphyria cutanea tarda (s-PCT), familial porphyria cutanea tarda (f-PCT), and hepatoerythropoietic porphyria (HEP). Subnormal UROD activity is due to mutations of the UROD gene in both f-PCT and HEP, but no mutations have been found in s-PCT. Genetic analysis has determined that f-PCT is transmitted as an autosomal dominant trait. In contrast, HEP, a severe form of cutaneous porphyria, is transmitted as an autosomal recessive trait. HEP is characterized by a profound deficiency of UROD activity, and the disease is usually manifest in childhood. In this study, a strategy was designed to identify alleles responsible for the HEP phenotype in three unrelated families. Mutations of UROD were identified by direct sequencing of four amplified fragments that contained the entire coding sequence of the UROD gene. Two new missense mutations were observed at the homoallelic state: P62L (proline-to-leucine substitution at codon 62) in a Portuguese family and Y311C (tyrosine-to-cysteine substitution at codon 311) in an Italian family. A third mutation, G281E, was observed in a Spanish family. This mutation has been previously described in three families from Spain and one from Tunisia. In the Spanish family described in this report, a paternal uncle of the proband developed clinically overt PCT as an adult and proved to be heterozygous for the G281E mutation. Mutant cDNAs corresponding to the P62L and Y311C changes detected in these families were created by site-directed mutagenesis. Recombinant proteins proved to have subnormal enzyme activity, and the Y311C mutant was thermolabile.

Incidence of hereditary porphyria cutanea tarda (PCT) in a sample of the Italian population.

The determination of the enzymatic activity of URO-D in erythrocytes is the screening method used for differentiation between hereditary and non-hereditary forms of porphyria cutanea tarda (PCT). The aim of the present work was to establish the relative frequencies of the symptomatic and hereditary forms by the determination of the URO-D enzyme in the PCT patients who were regularly treated at the Centre for Porphyrins in our Institute. In the course of this work we also examined the statistical properties of the distributions of both normal and porphyric subjects, so as to be able to suggest values for discriminating between normal subjects and the various types of porphyric subjects.

[Neurological, dermatological and biological manifestations of porphyria variegata. A study of 3 families of Italian origin in Marseilles area]. / Manifestations neurologiques, dermatologiques et biologiques de la porphyrie variegata, Etude de trois familles d'origine italienne vivant dans la région marseillaise.

Three kindreds of Italian descent with variegate porphyria are described. These families are now living in Marseilles and surrounding regions. The first kindred originating from Torre del Greco, near Naples, is living in Arles. This family includes two propositi who experienced an acute attack with visceral and neuropsychiatric manifestations. The family's survey was carried out by measuring protoporphyrogen oxidase (PO) activity in lymphocytes (normal values = 4.8 +/- 1.2). Seven of the 20 subjects tested, beside the two propositi, were found to be asymptomatic carriers (PO < 3.6). The first index patient, a 41-year old man, was first observed at the age of 31 with acute and psychiatric manifestations after rifampicin treatment; the cutaneous symptoms appeared one year later. For the second propositus, a woman presenting with abdominal and psychiatric manifestations, the age of onset was 38 years; the acute attack had no recognizable cause; she had mild skin lesions and initially was incorrectly diagnosed as intermittent acute porphyria; the diagnosis of variegate porphyria was only established at the age of 50 years. The second family, originating from la Spezia and Vernazza, is living in Marseilles. The propositus, a 50-year old man, developed cutaneous symptoms at the age of 30. A diagnosis of porphyria cutanea tarda was initially made. The first and unique acute attack with abdominal and neurological manifestations recurred at the age of 41. The diagnosis of variegate porphyria was established on laboratory data. Physical stress was probably the cause of the acute attack. Beside the propositus, out of 9 subjects tested 6 were asymptomatic carriers.(ABSTRACT TRUNCATED AT 250 WORDS)

[An unusual mechanism of lead poisoning. Presentation of a case]. / Inconsueta modalità d'intossicazione da piombo. Presentazione di un caso.

A case is described, that came to our attention for suspected acute intermittent porphyria, with abdominal pain and ascending tetraplegia. The patient (HIV positive and with a HBsAg positive chronic aggressive hepatitis) was a heroin addict. In urine: high porphyrins with extremely increased delta amino-levulinic acid (ALA) and normal porphobilinogen. High protoporphyrin was present in blood red cells. The lead poisoning was confirmed by a very low ALA-dehydratase activity in erythrocytes and a high content of lead in urine and plasma. With Ca-versenate and penicillamine the abdominal and neurological symptoms rapidly disappeared. The possibility of contact with lead, professional or environmental, was ruled out. It was found however, that shortly before the appearance of symptoms, the patient had used a batch of unrefined brown sugar heroin, which was probably mixed with lead salts. It is noteworthy that during the same period, other young heroin addicts died with similar symptoms.

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.

Hepatoerythropoietic porphyria.

A patient with hepatoerythropoietic porphyria had typical cutaneous manifestations: photosensitivity with blistering and mild scarring, and hypertrichosis. Biochemically elevated levels of protoporphyrins in erythrocytes, uroporphyrins in urine, and coproporphyrins in feces are markers of this form of porphyria. A family study confirmed that he was homozygous for a defect of uroporphyrinogen decarboxylase. A trial with hydroxychloroquine produced no improvement.

Porphyrins in Rotor's syndrome: a study on an Italian family.

Porphyrins in urine, plasma, erythrocytes and feces have been tested in two brothers affected by Rotor's syndrome and in three of their phenotypically normal relatives. In all five subjects normal values of delta-aminolevulinic acid and porphobilinogen in urine, and of prophyrins in plasma, erythrocytes and feces, were found. The two patients showed a marked increase in total urinary coproporphyrin excretion with a high percentage of isomer I. These observations confirm the hypothesis of a different route of the porphyrin excretion in Rotor's syndrome with a shift from the fecal route to the urinary one, and do not agree with the suggestion of an increased hepatic porphyrin production in this type of hyperbilirubinemia.

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.

Peripheral nerve findings in hereditary coproporphyria. Light and ultrastructural studies in two sural nerve biopsies.

In spite of several cases reported in the literature, the exact pathogenetic mechanism of neuropathic changes in porphyric neuropathy remains uncertain. Various authors have ascribed the neuropathologic findings to either a dying-back axonal degeneration or segmental demyelination. In recent years, the hypothesis of an axonal and myelinic disorder has received support by the demonstration of a combined and simultaneous involvement of both these structures. Such different opinions are also a consequence of the reduced number of detailed bioptic observations in the different forms of acute porphyria not only during acute phases but also between attacks. In this paper we report the results of light- and electron-microscopic examination of two sural nerve biopsies from subjects with hereditary coproporphyria. The first was performed 6 months after an acute attack, the second specimen was obtained from a patient without acute attacks, who had clinical and electrophysiologic signs of a chronic progressive neuropathy. In both cases a dying-back axonal degeneration is considered the primary change. The pathogenetic mechanism of peripheral nerve lesions in porphyric neuropathy will be discussed finally.

Hereditary coproporphyria: unusual nervous system involvement in two cases.

Two cases of hereditary coproporphyria showed unusual nervous system involvement, one epilepsy with onset in childhood, and the other chronic central and peripheral nervous system damage. The literature is briefly discussed.

Acquired cutaneous toxoplasmosis.

We examined more than 1,400 dermatologic patients with clinically defined (but having unknown or presumably multiple etiology) affections. The investigation revealed the presence of antitoxoplasma antibodies in more than 50% of the patients, but in only 11% of the cases did the serological analyses give evidence of an active form of disease. It was possible to prove the toxoplasmic etiology of 29 cases of chronic prurigo and of 4 cases of dermatocellulitis. The same infection was involved in a few cases of different dermatoses and in two cases of dermatomyositis-like syndrome. Pseudotumoral granulomatous localizations occurred in immunosuppressed patients. We suggest an 'immunological key' to explain the polymorphism of the cutaneous manifestations. The practical interest of this new knowledge and its importance as a field of interdisciplinary studies are emphasized.

[Zinc and porphyria cutanea tarda]. / Zinco e porfiria cutanea tarda (PCT).

In 30 patients affected by Porphyria Cutanea Tarda we determined: plasmatic, erythrocytary and urinary zinc (by atomic absorption spectrophotometry); total porphyrins in plasma and in urines, coproporphyrins and protoporphyrins in erythrocytes (by spectrophotometric methods); haptoglobin, hemopexin, alpha 2-macroglobulin and albumin (by immunological methods). The results obtained were compared with those of normal subjects. In addition, the variables under consideration were statistically analyzed to bring out possible correlations (both simple and partial). The most interesting result (besides the documentation of an increase in the urinary and plasmatic zinc in porphyric patients) was the finding of correlations between plasmatic zinc, plasmatic porphyrins and alpha 2-macroglobulin.