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PubMed1979

[Erythropoietic protoporphyria].

Erythropoietic protoporphyria (EEP) is the most frequently found erythropoietic porphyria in men. This inborn error of heme metabolism with autosomal dominant mode of inheritance is based on a deficiency of ferrochelatase. This defect leads to an increase for protoporphyrins predominantly in the red cells. Under the influence of sun light, especially UV-A, photohemolysis occurs and the content of protoporphyrin in the tissue increases. This is associated with acute sun burn like skin lesions, which usually clear up completely. Persistent skin lesions are seen in form of hyalinosis like infiltrations of the most intensively light exposed skin areas in some patients. Associated symptoms might be: gallstones or rarely a cirrhosis of the liver. Treatment with photoprotective ointments and especially carotinoids (beta-carotene, canthaxanthine) is very effective and only in some rare cases this symptomatic therapy fails. Prognosis of the disease is good. Only a few patients died of the associated hepatic failure.

Carotenoids↗
PubMed2025

Liver involvement in a large cohort of patients with erythropoietic protoporphyria or X-linked protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed. METHODS: Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described. RESULTS: A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at enrollment was 33.3 years. Liver chemistries were available for 235 patients, and 132 (56.2%) had abnormalities, mostly mild. Abnormal liver enzymes were associated with higher erythrocyte protoporphyrin levels. Eleven patients had advanced protoporphyric hepatopathy. In total, 54 (16.8%) underwent cholecystectomy, 8 (2.5%) had a liver transplant, 4 (1.2%) had a bone marrow transplant, and 8 (2.5%) died. At least 4 deaths were caused by liver failure due to protoporphyric hepatopathy, 2 were complications of bone marrow transplant, and 1 from HCC, which developed in a patient with EPP without cirrhosis. Patients with XLP were more likely to develop liver-related complications compared to EPP. CONCLUSIONS: Liver abnormalities are common in patients with EPP and XLP. In this national registry, only 3.4% had protoporphyric hepatopathy, with most requiring a transplant. Of the deaths, 62.5% were attributable to liver disease. Further observations are needed for guiding hepatic evaluation and management of patients with protoporphyria with or without initial hepatic abnormalities.

Humans↗
PubMed1976

Erythropoietic protoporphyria. Hepatic implications.

The terminal stages of erythropoietic protoporphyria are recorded. The observations are related to the site of the fundamental lesion and the nature of the biochemical defect. The possibly ominous prognosis in this usually mild condition is emphasized. Apart from congenital porphyria, the porphyrias do not usually confer severe cutaneous lesions. These diseases present to dermatologists because of moderate photosensitivity and are not usually regarded as a risk to life. Dangerous central nervous system involvement may occur, however, in acute intermittent, variegate and hereditary coproporphyrias, while in acquired symptomatic porphyria severe underlying liver dysfunction may occur. Probably the most common familial photosensitizing porphyria is erythropoietic protoporphyria. Recently some deaths from severe liver involvement have been reported in this disease.

Feces↗
PubMed1977

Comparative study of protoporphyrins in erythropoietic protoporphyria and griseofulvin-induced murine protoporphyria. Binding affinities, distribution, and fluorescence spectra in various blood fractions.

Excess erythrocyte protoporphyrins of human congenital erythropoietic protoporphyria and of griseofulvin-induced murine hepatic protoporphyria were found to be associated with hemoglobin and stroma fractions in similar relationships. More than 99.5% of total erythrocyte protoporphyrin was bound to hemoglobin in each case. However, profound differences were found when protoporphyrin concentration was measured in erythrocytes that had been segregated into populations of progressive age on discontinuous density gradients. In erythropoietic protoporphyria, porphyrin content diminished rapidly with age; in murine protoporphyria, the aging erythrocyte populations became progressively more porphyrin rich. In vitro diffusion of protoporphyrin from plasma across the intact erythrocyte membrane was demonstrated. The equimolar binding affinity of protoporphyrin to hemoglobin was shown to be 40 times that of protoporphyrin to serum albumin. This strong affinity provides the driving force for the observed transmembrane diffusion, and explains the high erythrocyte/plasma porphyrin ratio in murine hepatic protoporphyria. The opposite rapid efflux of intra-erythrocytic protoporphyrin into plasma previously shown in uncomplicated erythropoietic protoporphyria occurs despite this strong hemoglobin affinity, implying continuous efficient clearance of protoporphyrin from plasma by the liver. Furthermore, these and other data suggest that a hepatic synthetic source for any significant fraction of the blood protoporphyrin in erythropoietic protoporphyria is highly improbable.

Animals↗
PubMed1978

Hepatic failure and death from erythropoietic protoporphyria.

A 60-year-old white male presenting with a clinical picture of obstructive jaundice was subsequently found to have erythropoietic protoporphyria. The diagnosis was suspected because of a history of life-long photosensitivity and was confirmed by finding high levels of erythrocyte protoporphyrin. Liver biopsy revealed birefringent deposits of protoporphyrin by polarization microscopy accompanied by severe hepatic injury and fibrosis. The patient died rapidly from liver failure, and at autopsy the biliary tree was patent. Despite the autosomal dominant transmission of erythropoietic protoporphyria, we failed to detect any family members with the disease. This report is concluded with a brief discussion of the liver involvement in erythropoietic protoporphyria.

Cholestasis↗
PubMed1979

Studies in porphyria IX: Detection of the gene defect of erythropoietic protoporphyria in mitogen-stimulated human lymphocytes.

We have demonstrated in this study that mitogen-stimulated lymphocytes from EPP subjects accumulate substantially greater amounts of protoporphyrin IX than do normal lymphocytes when incubated with ALA. Protoporphyrin IX formation by normal lymphocytes is stimulated by CaMgEDTA, an inhibitor of ferrochelatase, and is decreased by ferrous iron which facilitates the utilization of protoporphyrin IX for heme synthesis. In contrast, protoporphyrin IX formation by EPP lymphocytes is less stimulated by CaMgEDTA than is the case with normal lymphocytes and is only slightly affected by iron. Clinically manifested EPP subjects and completely latent gene carriers of EPP can be identified using this lymphocyte culture technique. The data from this study provide clear evidence of a functional deficiency of ferrochelatase activity in human EPP lymphocytes. EPP thus represents the third of the three dominant porphyric disorders of man, including acute intermittent porphyria and hereditary coproporphyria, which can now be diagnosed using lymphocytes.

Adolescent↗
PubMed1977

In vitro studies on the protoporphyrin uptake and photosensitivity of normal skin fibroblasts and fibroblasts from patients with erythropoietic protoporphyria.

Fibroblasts derived from patients with erythropoietic protoporphyria (EPP) are not sensitive to violet light and do not contain an excess of protoporphyrin (PP). Fibroblasts from both normal individuals and patients with EPP can take up very low concentrations of PP from culture medium. Cells grown in PP-containing medium showed a gradually increasing but limited uptake of PP and also an increased sensitivity to light. A sensitive scanning microfluorometric method has made it possible to demonstrate that the PP is mainly localized in the perinuclear granules. After exposure to violet light, cells photosensitized by PP in a culture medium showed increased membrane permeability as well as reduced reproductive capacity. Both of these photodamage effects can be repaired during postirradiation incubation in culture medium at 37 degrees C.

Cell Division↗
PubMed1977

Porphyrin synthesis in blood cells of patients with erythropoietic protoporphyria.

The protoporphyrin accumulation observed in the red blood cells of patients with erythropoietic protoporphyria can be explained by decreased activity of the enzyme heme synthetase or by increased production of porphyrins in the affected cells. In literature experimental evidence both for a partial heme synthetase deficiency and for increased porphyrin biosynthesis has been presented. In a group of ten patients with erythropoietic protoporphyria the biosynthesis of porphyrins from delta-aminolevulinic acid and from glycine-succinic acid appeared to be normal in peripheral blood cells. These results are consistent with the partial heme synthetase deficiency previously found to be the basic defect of this disease.

Aminolevulinic Acid↗
PubMed1977

Photoprotection in erythropoietic protoporphyria: mechanism of photoprotection by beta carotene.

Erythropoietic protoporphyria is a genetic disease caused by the accumulation of protoporphyrin IX. This molecule absorbs 400-nm light and its presence is at times associated with severe cutaneous photosensitivity. The only effective treatment for this disease is oral administration of beta carotene. Several possible mechanisms of photoprotection by beta carotene were investigated using the photohemolysis of red blood cells as an in vitro model. Additional studies were done in an in vivo model which involves lethal hematoporphyrin photosensitization of white mice. The photoprotective effects of beta carotene were compared with those of alpha tocopherol, an agent which possesses some but not all the properties that have been implicated in explaining the known effectiveness of beta carotene. In the photohemolysis model, both compounds demonstrated partial protection. In hematoporphyrin-photosensitized mice, tocopherol showed some protection at high doses, while beta carotene showed greater protection at lower concentrations. Although these results suggest that photoprotective was due to free radical scavenging or singlet oxygen quenching, properties common to both agents, they do not rule out the possible role of 400-nm light absorption, a property of beta carotene alone.

Animals↗
PubMed1977

Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases.

We treated with high doses of oral beta carotene (Solatene) (15 to 180 mg/day) 133 patients suffering from erythropoietic protoporphyria (EPP), 27 patients with polymorphous light eruption, six patients with solar urticaria, three patients with hydroa aestivale, one patient with porphyria cutanea tarda, and two patients with actinic reticuloid to relieve the photosensitivity associated with these diseases. Eighty-four percent of the patients with erythropoietic protoporphyria increased by a factor of 3 or more their ability to tolerate sunlight. On the other hand, only nine of the patients with polymorphous light eruption, and one fifth of the patients with all of the other forms of photosensitivity treated showed similar improvement. We conclude that beta carotene is an effective treatment for EPP, but that other forms of photosensitivity will need empirical therapeutic study with beta carotene to determine the range of effectiveness, if any, of this compound in conditions other than EPP.

Adult↗
PubMed1977

Binding of Protoporphyrin to hemoglobin in red blood cells of patients with erythropoietic protoporphyria.

Virtually all protoporphyrin in erythrocytes of patients with erythropoietic protoporphyria is bound to hemoglobin. The maximum of the fluorescence excitation spectrum of this protoporphyrin-hemoglobin complex shifted, with increasing concentration, from 405 nm to 389 nm. A similar shift was observed when titrating a solution of free protoporphyrin with hemoglobin. The Soret maximum of free protoporphyrin itself, on the other hand, was not concentration-dependent. These observations indicate that spectrofluorometric measurements do not allow conclusions concerning the mode of protoporphyrin binding to hemoglobin. Experiments on protoporphyrin exchange between the hemoglobins A, F and S reinforced the previously drawn conclusion that protoporphyrin is bound to hemoglobin at the heme-binding sites.

Binding Sites↗
PubMed1979

Beta-carotene in erythropoietic protoporphyria: 5 years' experience.

36 patients from 19 families with erythropoietic protoporphyria were treated for about 5 years during the summer months with beta-carotene alone or beta-carotene plus canthaxanthin in daily doses of 50-200 mg. The effect of the treatment was evaluated clinically on the basis of information provided by the patients regarding the period of time they could stay in the sun. 18 patients became completely free of symptoms, 16 patients improved to some extent, and 2 patients noted a slight effect. Apart from the carotenaemia, no side-effects were recorded.

Adolescent↗
PubMed1978

Porphyrin production and liver involvement in a patient with erythropoietic protoporphyria.

The clinical and biochemical findings in a patient with erythropoietic protoporphyria are described. The patient had an extreme accumulation of protoporphyria in his erythrocytes and there was a thirty-fold increase in stool protoporphyrin. The patient also had elevated protoporphyrin in serum, bone marrow and liver. The porphyrins of the red blood cells, bone marrow and serum had fluorescence spectra different from that of the liver. Urine showed increased copra-, hepta- and uroporphyrins. Ferrochelatase activity in the bone marrow was less than 20% of that of non-porphyric controls. In spite of the extremely high levels of red cell protoporphyrin, the patient was clinically healthy with modest changes in liver function tests and liver histology. The results are discussed in relation to the development of liver damage and the recent findings of the effect of porphyrins on cell metabolism.

Adult↗
PubMed1978

Erythropoietic protoporphyria, heterozygous cystinuria, and reduced peptidase A activity in a patient with 46,XX/46,XX,18q--mosaicism.

An interesting patient with a deletion of the long arm of chromosome 18 is presented. Her symptoms are severe in comparison with some other 18q--patients, yet she was found to have a mosaicism with a normal 46,XX karyotype in about 20% of her cultured lymphocytes. In addition, she had erythropoietic protoporphyria, was heterozygous for type II or III cystinuria, and had reduced levels of peptidase A activity. Detailed studied on the patient, her family, and two additional 18q--patients suggest that the association with erythropoietic protoporphyria is coincidental and that the cystinuria gene was inherited from the patient's father. The reduced peptidase A activity, however, supports earlier observations that the peptidase A locus maps in the q22 to terminus region of chromosome 18.

Child↗
PubMed1977

The treatment of erythropoietic protoporphyria. Experience with beta-carotene.

In a group of 19 subjects suffering from erythropoietic protoporphyria the administration of beta-carotene appeared to produce improvement based on a subjective assessment of alterations in exposure times required to produce the symptoms and signs of the condition. This clinical improvement however failed to show a direct correlation with the prophyrin levels in blood and faeces, or with the estimation by phototesting of the minimal response dose within the action spectrum of 400-600 nm.

Adolescent↗
PubMed1978

Erythropoietic protoporphyria: hepatic cirrhosis.

Observations on liver pathology and function were made on 12 patients with erythropoietic protoporphyria (EPP). Needle liver biopsies in 3 of 11 patients showed mild portal or periportal fibrosis without evidence of abnormal liver function. One patient (Case 12), died from hepatic cirrhosis and failure at the age of 11 years, the youngest yet reported. He was not suspected of pending liver disease until 3 months before death. The quantity of protoporphyrin present in his liver was approximately 5.75% of total liver weight. Fatal liver disease in EPP has occurred in 13 patients, 7 male and 6 female, in which the mean age of death was 38 years. The pathology of the liver in EPP is characteristic and is described.

Adolescent↗