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PubMed2000

Erythropoietic and hepatic porphyrias.

Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10%, of patients. Acute hepatic porphyrias (delta-aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological-psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life-threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic delta-aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic delta-aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased metabolites upstream of the enzymatic defect are excreted into urine and faeces. The diagnosis is based on their evaluation. Primary enzymatic or molecular analyses are noncontributary and may be misleading. Acute polysymptomatic exacerbations accompany a high excretory constellation of porphyrin precursors delta-aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.

Animals↗
PubMed1999

Studies on coproporphyrin isomers in urine and feces in the porphyrias.

The urinary and fecal distribution and the relative proportions of the four coproporphyrin (copro) isomers I-IV were analysed in 20 healthy subjects and in patients suffering from one of the seven common types of hepatic or erythropoietic hereditary porphyrias. The ratios of copro isomers I-IV were analyzed by ion-pair high-performance liquid chromatography (HPLC). Observations showed significantly increased proportions of fecal copro isomer I and decreased proportions of copro isomers III, II and IV in erythropoietic porphyrias. In acute hepatic porphyrias the excretion of fecal copro isomer III is dominant (isomer III = 58.4+/-24.0%; x+/-S.D.) and significantly higher (P < 0.001) than in erythropoietic porphyrias (isomer III = 15.3+/-7.7%; x+/-S.D.) and chronic hepatic porphyrias (isomer III = 25.8+/-7.6%; x+/-S.D.). The increased proportions of fecal copro isomer III proved to be important for the diagnosis of hereditary coproporphyria and porphyria variegata independent of the clinical phase existing. These last two acute hepatic porphyrias also showed markedly elevated percentages of the fecal atypical isomers II and IV. In urine significantly decreased proportions of copro isomer I in acute hepatic porphyrias (isomer I = 12.3+/-6.0%; x+/-S.D.) could be observed as compared with non-acute porphyrias (isomer I = 53.7+/-15.2%; x+/-S.D.). Conversely, the proportion of urinary copro isomer III was significantly higher in acute hepatic porphyrias (isomer III= 81.4+/-6.4%; x+/-S.D.). As expected, the greatest amounts of urinary copro isomer I were found in congenital erythropoietic porphyria (isomer I =92.0+/-3.3; x+/-S.D.) and protoporphyria with hepatobiliary complications (isomer I = 81.3+/-10.7; x+/-S.D.). The atypical urinary copro isomers I1 and IV were detected in all types of porphyrias ranging from 0.1 to 11.5%. The combined amounts of copro isomers II and IV show a significantly decreased percentage in congenital erythropoietic porphyria as compared with all other types of hereditary porphyrias. In conclusion, we demonstrate that the characteristic pattern of the copro isomer constellations I-IV in the various types of porphyrias are of differential diagnostic importance. The inversion of the I to III ratio in feces in hereditary coproporphyria and porphyria variegata allows the recognition of gene carriers.

Chromatography, High Pressure Liquid↗
PubMed1995

The difference in liver pathology between sporadic and familial forms of porphyria cutanea tarda: the role of iron.

Porphyria cutanea tarda is a disorder of porphyrin metabolism, of which familial and sporadic forms have been described. Factors such as iron seem necessary for porphyria cutanea tarda to become clinically manifest. To study the relationship between iron and uroporphyrins in hepatocytes of patients with porphyria cutanea tarda, a morphological and morphometrical study was performed in 13 liver biopsies of patients with porphyria cutanea tarda (eight with sporadic porphyria cutanea tarda and five with familial porphyria cutanea tarda). In addition, possible differences in clinical and biochemical features and in histopathological findings between patients with sporadic porphyria cutanea tarda and familial porphyria cutanea tarda were investigated. Familial porphyria cutanea tarda patients presented at a younger age than sporadic porphyria cutanea tarda patients (42.4 +/- 5.3 vs. 57.3 +/- 8.6 years). Biochemical features were not different between sporadic porphyria cutanea tarda and familial porphyria cutanea tarda patients. Uroporphyrin crystals and a variable degree of liver siderosis were detected in the biopsies of all 13 patients. Uroporphyrin crystals were often found close to ferritin-like iron deposits. The morphometrical analysis showed that an increased mean area fraction of ferritin iron was associated with an increased mean area fraction of uroporphyrin crystals in hepatocytes of sporadic porphyria cutanea tarda and familial porphyria cutanea tarda patients. Moreover, the amount of uroporphyrin crystals was significantly higher in livers of familial porphyria cutanea tarda than sporadic porphyria cutanea tarda patients. These findings are consistent with the hypothesis that uroporphyria is precipitated by an iron-dependent process.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1979

The porphyrias.

The heterogeneous group of diseases called the porphyrias may all be characterised by derangement of specific stages in the haem biosynthetic pathway. In the acute porphyrias; acute intermittent porphyria, urophorphyrinogen 1 synthase, hereditary coproporphyria, coproporphyrinogen oxidase and variegate porphyria, ferrochelatase or protoporphyrinogen oxidase, are the enzymes affected, whilst in the non acute porphyrias, cutaneous hepatic porphyria, uroporphyrinogen decarboxylase, congenital porphyria, uroporphyrinogen cosynthase; and erythropoietic protoporphyria; ferrochelatase are the enzymes affected. In each of the porphyrias, the activity of the initial and rate controlling enzyme of the pathway, delta-aminolaevulinic acid synthase is raised which constitutes the principal control point of the pathway. Secondary control in each of these diseases lies at the leve of uroporphyrinogen 1 synthase. As a consequence of this secondary control, there is excessive excretion of the porphyrin precursors delta-aminolaevulinic acid and porphobilinogen in the acute porphyrias and excessive excretion of porphyrins leading to solar photosensitivity in the non-acute porphyrias and in variegate and hereditary coproporphyria. There are a number of secondary metabolic aspects in the porphyrias, such as the role of steroid metabolism; the influence of drugs in the potentiation of attacks; and the potential for the pathway to branch at stages prior to porphyrin formation which result in the synthesis of various monopyrroles. The therapy of the two groups of porphyrias are quite different. Prophylaxis is important in both types but is particularly important in the avoidance of various drugs in the acute porphyrias. The acute attack may be specifically treated with carbohydrates, beta-blockers and haematin. Cutaneous hepatic porphyria may be treated by venesection, erythropoietic protoporphyria with beta caratene whilst congenital porphyria may be improved by splenectomy and chloroquine therapy.

5-Aminolevulinate Synthetase↗