Urinary porphyrin excretion measurements in healthy neonates.

The objective of this study was to establish normal reference ranges for porphyrins in healthy neonates. There is little information about urinary porphyrin excretion in this age group. This knowledge may provide an early diagnostic tool for detecting subtle alterations or latent forms in disorders of heme biosynthesis. Fifty healthy neonates were selected from the Department of Obstetrics. Total urinary porphyrins in random specimens were analysed by a spectrofluorometry method. The measurement of porphyrin fractions was made by fluorometric high-performance liquid chromatography (HPLC). The results were adjusted to urinary creatinine excretion to correct any imprecision and interindividual variation in body mass. The urinary total porphyrin had a median value of 331.50 (nmol/L). A statistically significant relationship between total porphyrin (nmol/L) and creatinine (mmol/L) was found (p < 0.01). The porphyrin/creatinine ratio showed a median value of 56.30 nmol/mmol creatinine. The study of individual porphyrins revealed that coproporphyrin and uroporphyrin were the major porphyrins excreted in neonates (coproporphyrin represents 81.98% and uroporphyrin 16.64% of total porphyrin); in both cases, isomer I was predominant with median values of 22.36 and 6.25 nmol/mmol creatinine, respectively. No significant relationships were found between porphyrin excretion and sex, gestational age, weight, or height. Our data provide the reference limits for porphyrins in neonates as a diagnostic guideline for evaluation of subtle alterations in heme biosynthesis.     

Effect of oral contraceptives on urinary porphyrins

Several studies have reported on the appearance of cutaneous porphyria in people treated with estrogen. This study was undertaken to investigate the effects of oral contraceptives (OCs) on levels of porphyrins in urine in nonporphyric women. 30 women aged 21-40 and on OCs were observed as the study group, and 10 women using other contraceptive methods were observed as the control group. Urinary porphyrins were measured by the Remington method. Levels of urinary coproporphyrin and of urinary uroporphyrin were higher in the study group than in the control group. These differences, however, are not statistically significant. To study the effect of duration of OC treatment, women who had taken OCs for 3-6 months and women who had taken OCs for longer than 6 months were observed, and the means of urinary coproporphyrin and uroporphyrin measured. Again, the differences were found to be insignificant, although slightly higher values of urinary coproporphyrin were obtained for women who had been on OCs for a longer period. These results compare favorably with others reported in the published literature. It can be concluded that OC treatment has no significant bearing on porphyrin metabolism.     

Porphyrin concentrations in various human tissues

Abstract We measured the concentrations of total porphyrins and their metabolites (uro-, hepta-, hexa-, penta-, copro- and protoporphyrin) in various human tissues: liver, erythrocytes, skin, adipose tissue, and mammary gland. The porphyrin concentrations varied within minor limits, e.g., 3.1 ±2.3 nmol porphyrins/g liver and 0.50±0.10 nmol/g erythrocytes. No significant differences were detectable in other tissues in comparison with liver. In all tissues, the predominant metabolite was protoporphyrin, followed by coproporphyrin, whereas only low concentrations of higher carboxylatcd porphyrins such as uroporphyrin were detectable. It is concluded that porphyrin metabolism and its regulation is similar in all human tissues, perhaps with some small differences in the erythrocytes.     

Porphyria cutanea uraemica: an obligate systemic disease in chronic kidney insufficiency?]

Patients with chronic renal failure, especially those receiving maintenance haemodialysis, have a number of dermatological alterations. Some of them are similar to those seen in porphyria cutanea tarda (PCT). Whereas early studies showed normal plasma porphyrin levels, a striking elevation of plasma porphyrins, and particularly of uroporphyrin, has recently been found. We measured the concentrations of porphyrins in the plasma and erythrocytes of 55 patients with chronic renal failure and receiving maintenance haemodialysis and also in 7 patients with PCT and 100 healthy volunteers. The mean concentration of porphyrins in plasma was 2.7-fold, and the maximum concentration, 6-fold the highest value measured in plasma of controls. The mean plasma concentration of uroporphyrin was 6-fold higher up to a maximum value of 37-fold the upper limit of the controls. The plasma porphyrin values of 3 of 7 patients with PCT were on the same high level as those measured in patients undergoing haemodialysis. The mean porphyrin concentration in the erythrocytes of haemodialysis patients were 1.5-fold the control values. Because of the known pathophysiological effect of uroporphyrin, especially its stimulation of the collagen synthesis and the activation of the complement system, we suppose that the porphyria cutanea tarda like skin lesions in patients with chronic renal failure are due to the highly increased uroporphyrin concentration.     

Urinary porphyrin analyses in patients with porphyria cutanea tarda

Urinary porphyrin analyses were carried out in five patients with porphyria cutanea tarda and in a control group of 44 individuals. Quantitative analysis revealed that the mean value of coproporphyrin was 67.3 μg/l (range 13.1–189.1 μg/l) in 44 normal individuals and the mean value of uroporphyrin was 9.7 μg/l (range 5.0 to 13.7 μg/l) in 11 of 44 controls, but not detectable in the remainder. Four of the five patients with porphyria cutanea tarda, however, had markedly elevated coproporphyrin and uroporphyrin levels. Urinary porphyrin pattern analysis was carried out using one dimentional thin layer chromatography. The pattern in controls revealed that the mean value of coproporphyrin was 85.5%, while the other fractions consituted less than 6.0%. In the porphyria cutanea tarda group, however, hepta-carboxyl porphyrin and uroporphyrin were predominant in two; all five fractions appeared in roughly equal amounts in one; and in the remaining two, coproporphyrin was decreased to a value of only about 50%. A patient treated by phlebotomy was also evaluated by this method. His urinary porphyrin pattern showed a shift from uroporphyrin to a high concentration of coproporphyrin during and after the treatment. With this method, it is very simple to obtain data for urinary porphyrin pattern analysis, and many samples can be analyzed simultaneously. The profile can aid in the diagnosis of porphyria cutanea tarda, especially when the patients show low levels of urinary porphyrins quantitatively.     

Patterns of porphyrin-excretion in female estrogen-induced porphyria cutanea tarda

Summary It has been suggested that the urinary profile of porphyrins excreted by female patients with estrogen-induced porphyria cutanea tarda is peculiar in that heptacarboxylic porphyrin equals or exceeds uroporphyrin.The chromatographic pattern of urinary porphyrin excretion was studied in nine females with porphyria cutanea tarda precipitated by estrogens, 129 porphyric males, and nine females, whose porphyria was not hormone-induced. Both female porphyric groups showed absolutely the same urinary chromatographic pattern and looked quite similar to the pattern observed in male patients. None of our female porphyric patients, whether treated with estrogens or not, showed percentage values for the heptacarboxylic porphyrin higher or equal to the uroporphyrin values.Our results do not support the hypothesis that the profile of urinary porphyrin excretion found in estrogen-induced porphyria cutanea tarda is atypical.     

Porphyria cutanea tarda (PCT) in a patient with chronic renal failure on haemodialysis

Porphyria cutanea tarda, diagnosed by reduced levels of red cell uroporphyrin decarboxylase and raised plasma porphyrins, developed in a patient with chronic renal failure due to polycystic kidneys, treated with haemodialysis, who had normal total urinary and faecal porphyrins. Haemodialysis did not alter plasma porphyrin levels and we deduced that most of the plasma porphyrins were circulating in high molecular weight protein complexes.     

Iron absorption during the development of hexachlorobenzene-induced porphyria in rats

Summary The absorption of iron [⁵⁹Fe-(FeSO₄)] from jejunal loops was studied in rats after acute and subacute exposure to hexachlorobenzene (HCB). Female rats were given orally 100 mg HCB/kg body weight or fed a diet with 0, 500, 1,000, or 2,000 parts/10⁶ HCB for 1 and 4 weeks. Male rats were fed on diets with 0 and 2,000 parts/10⁶ HCB only. An increase in total urinary porphyrins and a decrease in the ratio of coproporphyrin to uroporphyrin in individual 24-h urine samples indicated different stages of porphyria in the rats at the time of determination of iron absorption. After acute oral administration of HCB, iron absorption decreased to about 70% of control values. After feeding the animals on HCB-containing diets, relative liver weight as well as total plasma protein increased depending on time and dose. The absorption of iron was not altered after 1 week of HCB exposure. After 4 weeks, the uptake of iron into the carcass decreased to less than 40% of control values, independently of dose and sex. The uptake of iron into the liver, expressed as percentage of the amount absorbed by the intestine, decreased significantly after 1 and 4 weeks of HCB feeding. No correlation could be observed between iron metabolism and urinary porphyrin excretion. The development of HCB-induced porphyria in rats is apparently not accelerated by an increased iron absorption.     

Latent porphyria cutanea tarda

A total of 142 subjects have been examined; of these 49 healthy relatives of patients with manifest porphyria cutanea tarda (PCT) (group 1), 48 subjects with melanodermal skin changes characteristic of PCT abd with anamnesis aggravated for alcoholism (group 2), and 45 patients with chronic liver diseases (group 3). None of the examinees has developed photosensitization symptoms. The findings have been compared to the results of examinations of 24 normal subjects and of 145 patients with manifest PCT. Minimal abnormalities of porphyrin metabolism have been detected in 43 subjects (30.2%). In group 1 subjects these abnormalities presented as increased levels of uroporphyrin and fecal coproporphyrin, in Groups 2 and 3 as secondary coproporphyrinuria and a symptomatic rise of fecal protoporphyrin level. Latent PCT has been diagnosed in 18 patients (12.7%). In latent PCT the total porphyrin excretion with the urine has been 10-fold lower than in manifest PCT, not exceeding 1000 nmol/day; in has been associated with a relative elevation of uroporphyrin level (up to 42-65% of the total porphyrin content). Increased coproporphyrin concentrations have been recorded, with coproporphyrin share making up over 60% of the total amount. It is possible that the minimal shifts of porphyrin metabolism anticipate the development of the biochemical syndrome of latent PCT. The author suggests criteria for the early diagnosis of the latent forms of the disease. He considers that the examinees should be referred to a group at risk of developing manifest PCT.     

Porphyria cutanea tarda in a chronic hemodialysis patient

About 3 years after commencing hemodialysis for chronic renal failure, a 39-year-old man developed cutaneous lesions of the face and hands which were compatible with porphyria cutanea tarda (PCT) clinically and histologically. There was no evidence of familial PCT, excessive alcohol consumption, iron overload, chronic liver disease. It was impossible to measure urinary porphyrins because of anuria. Fecal and erythrocytic porphyrins were within normal limits. Plasma porphyrins, however, were markedly elevated, and in an assay using high performance liquid chromatography, uroporphyrin accounted for 72% and 7-carboxyl porphyrin for 24%. Review of past reports of PCT associated with hemodialysis revealed that the most characteristic feature was a significant increase of plasma porphyrins, mainly uroporphyrin. This increase is difficult to explain by accumulation due to failure of adequate clearance. Participation of factors affecting uroporphyrinogen decarboxylase activity seems likely.     

Interdependence between degree of porphyrin excess and disease severity in congenital erythropoietic porphyria (Günther’s disease)

Various clinical and biochemical observations point to a relationship between degree of disease expression and metabolic disturbance in autosomal recessive congenital erythropoietic porphyria (Günther’s disease). Although the clinical manifestations have been well described since Günther’s fundamental observations, an interdependence between disease severity and porphyrin excess has yet to be elucidated. We investigated porphyrin metabolism in nine Indian patients suffering from the characteristic clinical symptoms: skin photosensitivity, red-colored urine as a sign of extremely elevated porphyrinuria and mild to severe hemolytic anemia. Porphyrins in urine, feces and blood were analysed by HPTLC and HPLC in conjunction with spectrophotometry and spectrofluorometry. Uroporphyrinogen III synthase activities in red blood cells were determined using a coupled-enzyme assay. Biochemical studies revealed varying degrees of porphyrinuria with total urinary porphyrins between 23 and 102 μmol/24 h (normal <0.2 μmol/24 h) and uroporphyrin predominance. Urinary and fecal coproporphyrin isomer I were markedly elevated to 87– 97% and 81–93% (normal <31%, <75%), respectively. Overproduction of porphyrins led to a considerable porphyrinemia with mainly copro- and protoporphyrin. A hitherto undescribed fecal porphyrin pattern with increased protoporphyrin levels was found in three patients. This atypical finding was probably related to severe hemolysis since protoporphyrin can be excreted only via the liver with bile in the feces. High porphyrin levels in urine, feces and blood were associated with worse cutaneous symptoms. Activities of uroporphyrinogen III synthase in red blood cell lysates were decreased to between 9% and 30% of controls. Patients showed increased porphobilinogen deaminase activities, up to 190% of control. Deficiency of uroporphyrinogen III synthase activity was reflected by inversion of the relationship between and isomer III leading to dominance of isomer I. Elevation of porphobilinogen deaminase activities is related to hemolysis and, additionally, to regulatory compensation for the enzyme deficiency. Variations in both the severity of photosensitivity and the enhancement of porphyrin production and excretion indicate the molecular heterogeneity of this disease. These findings suggest a close relationship between the metabolic disturbance reflected by porphyrin excess and the severity of disease expression. Received: 12 July 1996     

Congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) is one of the rarest autosomal-recessive disorders of the porphyrin metabolism caused by the homozygous defect of uroporphyrinogen III cosynthase. High amounts of uroporphyrin I accumulate in all cells and tissues, reflected by an increased erythrocyte porphyrin concentration and excretion of high porphyrin amounts in urine and feces. Dermal deposits of uroporphyrin frequently induce a dramatic phototoxic oxygen-dependent skin damage with extensive ulcerations and mutilations. Splenomegaly and hemolytic anemia are typical internal symptoms. Skeletal changes such as osteolysis and calcifications are frequent. Up to date 130 cases of CEP have been published. Splenectomy and erythrocyte transfusions showed some beneficial effect. Bone marrow transplantation was performed in 3 patients and stem cell transplantation in 1. The best therapy is the avoidance of sunlight. We give a report on our latest cases of CEP.     

Administration of oral activated charcoal in variegate porphyria results in a paradoxical clinical and biochemical deterioration

BACKGROUND: Porphyrinogens are the obligate intracellular precursors of haem. These compounds are, however, unstable and are easily oxidized to the corresponding porphyrins, which are the form in which they are usually measured in the laboratory. A substantial enterohepatic cycling of porphyrins has been shown. Administration of oral activated charcoal, by interrupting this cycle, may reduce plasma and urine porphyrin levels in patients with some forms of porphyria. The effect of charcoal in subjects with variegate porphyria (VP) has not been reported. OBJECTIVES: To determine the clinical and biochemical effects of the administration of oral activated charcoal in patients with VP. METHODS: Oral activated charcoal was administered to eight subjects with VP. Clinical activity was assessed by skin lesion counts fortnightly for 6 weeks, 6 weeks after cessation of therapy, and during a subsequent 6-week control period during which no charcoal was taken. Urine and plasma porphyrins and urine precursors were measured by standard techniques. RESULTS: Treatment resulted in a significant increase in skin disease, urine and plasma porphyrins. CONCLUSIONS: Oral charcoal administration results in a paradoxical aggravation of VP, suggesting a complex and as yet undefined interaction of hepatic porphyrin metabolism and bowel porphyrin reabsorption. Oral sorbents should not be prescribed to subjects with VP.     

Porphyrin-sensitized cutaneous photosensitivity: pathogenesis and treatment

The purpose of this review is to examine in some detail the subject of the array of cutaneous lesions that occur in association with disorders of porphyrin-heme metabolism. In order to develop a broad understanding of the types of lesions that occur in the various disorders, of current concepts of their pathogenesis, much of which remains theoretical and speculative, and of approaches to therapy of these lesions, associated topics will be discussed.This review will only briefly touch on discussions of the enzymatic defects responsible for the various porphyric syndromes, laboratory approaches to accurate diagnosis, and associated systemic symptoms of these disorders and their treatment. For detailed reviews of these topics, the reader is directed to the other contributions in this issue that are more specifically aimed at these considerations.All porphyrias, with the exception of acute intermittent porphyria, include some form of cutaneous photosensitivity as a major manifestation among their associated clinical symptoms. Two general patterns of abnormal skin changes attributable to the interactions of porphyrins and light within the skin are recognizable. One or the other of these patterns is considered to be more characteristic for each of the disorders of porphyrin metabolism that exhibit photosensitivity, although there are instances in which some degree of combination of features of both types of abnormal skin changes appear to occur in the same patient or in different patients with the same porphyric disorder.The first reaction pattern is a painful, rapidly evolving, phototoxic response. The second pattern develops slowly and is usually initially painless, but is eventually much more destructive. Blistering, erosions, and scarring are the most typical clinical lesions of this second general response pattern.Whether cutaneous photosensitivity is a manifestation of any of the several distinct porphyric syndromes, or not, the differences in types of skin lesions displayed by patients with different forms of porphyrias are apparently determined chiefly by the physicochemical properties of the different porphyrins or porphyrin precursors that accumulate in each disorder. In turn, the various physical and chemical properties of the intermediaries of heme biosynthesis that accumulate in the several forms of porphyrias are determined by their molecular structures.     

Biochemical study of fecal porphyrin in porphyria cutanea tarda

Fecal, urinary and erythrocyte porphyrin analyses using the solvent extraction method were performed in 26 patients with porphyria cutanea tarda (PCT) and 144 normal controls. The levels of fecal uroporphyrin (UP) and coproporphyrin (CP) were markedly increased in the PCT group, especially in comparison with the protoporphyrin (PP) level. The values of the UP/PP and CP/PP ratios in the feces were also elevated over those in the control group. It appears that fecal porphyrin excretion is basically similar to urinary porphyrin excretion in PCT. The analysis of fecal porphyrins and the observation of fecal UP/PP and CP/PP ratios may be helpful in the biochemical diagnosis of PCT. In particular, the elevation of CP/PP ratio is characteristic of PCT.     

Hematologic and hepatic manifestations of the cutaneous porphyrias

This chapter has dealt with five photocutaneous forms of human porphyria. The forms are a diverse group of disorders with many different hematologic, hepatologic, and neurologic manifestations. In essence, most photocutaneous porphyrias occurring in childhood will relate to congenital erythropoietic porphyria or protoporphyria. The nature of the skin lesions and a study of the heme precursor profile in red cells, plasma, urine, and feces should easily distinguish these two conditions. CEP is a disease wherein photomutilation is a dominant concern and aggressive new approaches of therapy also have been discussed. In protoporphyria, the dermatologic problem is less severe and the dermatologist should be aware that a subset of patients could develop active liver disease that may lead to fatal cirrhosis. Novel approaches of therapy have been briefly alluded to. With regard to postpubertal photocutaneous porphyria, the classic porphyria cutanea tarda syndrome is associated with liver disease, usually alcoholic with siderosis, and the treatment by phlebotomy to reduce hepatic iron is highly effective. The potential danger of liver carcinoma has been discussed. In subsets of porphyria cutanea tarda, this can be an endemic disease relating to environmental factors, ie, ingestion of polyhalogenated hydrocarbons. The biochemical diagnosis can be attained by fairly straight-forward solvent extraction analyses of urine and feces, showing the dominance of uroporphyrin excretion in the urine and coproporphyrin in the feces. Chromatographic techniques in plasma, bile, and feces reveal a PCT-specific porphyrin: isocoproporphyrin. Rare subtypes with hematologic manifestations, ie, hepatoerythropoietic porphyria and CEP, indicate the wide spectra of disorders that might be associated with a spontaneous deficiency of uroporphyrinogen decarboxylase activity. These latter syndromes are, however, rare. Two hereditary hepatic porphyrias, ie, autosomal dominantly inherited VP and HCP, have been briefly discussed. The hepatic lesion is metabolic, not morphologic, and its expression by the liver relates to its adaptive response to induction of microsomal hemoproteins by a variety of exogeneous and endogeneous compounds, eg, drugs and hormones. Photocutaneous lesions of HCP and VP are identical to PCT, the latter having no neurologic sequelae. In the former two, however, exposure of persons to drugs, such as the hydantoins and barbiturates, can lead to potentially fatal acute porphyric attacks.(ABSTRACT TRUNCATED AT 400 WORDS)     

Porphyrin metabolic disorders in porphyria cutanea tarda

Altogether 98 patients have been examined, suffering from latent porphyria (n = 18) and manifest porphyria cutanea tarda (n = 80). 90 (91.8%) examinees abused alcohol. Clinical manifestation of the disease is associated with an essential rise of the blood plasma and urine uroporphyrin. Three types of porphyrinemia have been detected in the patients with manifest porphyria cutanea tarda, these types related to the degree of uroporphyrin level increase in the blood plasma and to the length of the disease: (I) uroporphyrinemia, (II) urocoproporphyrinemia, (III) urocoproprotoporphyrinemia. Porphyrinemia types are estimated as successive stages in the development of porphyrin metabolism disorders and are regarded among the criteria determining the clinical pattern of manifest porphyria cutanea tarda.     

Five cases of porphyria cutanea tarda with mild cutaneous changes: evaluation of the efficacy of phlebotomy by the pattern analysis of urinary porphyrins

Five cases of porphyria cutanea tarda (PCT) with mild cutaneous changes are reported. Acute episodes of photosensitivity were not seen in all patients. Laboratory examinations showed a predominance of uroporphyrin (UP) excretion in the urine in 4 out of 5 cases. One case showed a relatively low urinary porphyrin level even though abnormality of the porphyrin pattern was present. Four cases showing a predominance of UP excretion in the urine revealed a high level of serum coproporphyrin (CP) as well. Histopathologically, all cases showed a deposition of PAS positive materials surrounding the small blood vessels in the upper dermis, in addition to the deposition of IgG materials visualized by the immunofluorescent technique. Phlebotomy was performed fifteen times in one case. The urinary porphyrin level was gradually reduced to normal levels and the urinary porphyrin pattern shifted from a predominance of UP and hepta-carboxyl porphyrin to a predominance of CP excretion. Analysis of the urinary porphyrin profile is useful as a laboratory tool for diagnosis or observation of the course of PCT, as well as for the quantitative analysis of urinary porphyrins.     

Influence of topical photodynamic therapy with 5-aminolevulinic acid on porphyrin metabolism

Photodynamic therapy (PDT) with topically applied 5-aminolaevulinic acid (5-ALA) is increasingly used for treating tumours. The efficacy of topical PDT is limited to superficial and initial tumours. The topically applied doses of 5-ALA vary from 0.02 to 7.0 g per session according to the type of lesion. There are no studies on the influence of topically applied 5-ALA on the systemic accumulation of porphyrins or porphyrin precursors. A group of 20 patients with actinic keratoses (AK) and basal cell carcinomas (BCC) were treated by topical PDT with 5-ALA. Prior to and 6 and 24 h after PDT, 5-ALA and total porphyrin concentrations were determined in red blood cells and plasma, respectively. In addition, before and after 5-ALA treatment, 24-h urine samples were collected and porphyrins and porphyrin precursors were measured. There was no significant alteration in porphyrin metabolism. In some patients, a slight but insignificant increase in erythrocyte and plasma porphyrins was found 6 h after 5-ALA PDT. This investigation confirms clearly the safety of this treatment modality and demonstrates that 5-ALA application (up to 7 g) in the course of PDT has no influence on the concentrations of porphyrins and porphyrin precursors measured in various compartments.     

The porphyrias

The porphyrias are a group of disorders of heme metabolism that result from partial defects in the several enzymes that control heme biosynthesis. Accumulation of porphyrins or porphyrin precursors in several different patterns results from these defects and biochemically characterizes each specific syndrome. Patterns of cutaneous photosensitivity and associated systemic symptoms among the several porphyrias result from the types of porphyrins or precursors accumulated in each.