Studies in porphyria. VIII. Relationship of the 5 alpha-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intermittent porphyria.
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Adolescent↗
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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↗
Porphyrias: Pathophysiology and clinical management recommendations for hepatologists.
In humans, an enzyme dysfunction in heme biosynthesis results in a heterogenous group of diseases collectively known as porphyrias. From a clinical standpoint, porphyrias can be classified as erythropoietic (congenital erythropoietic porphyria-CEP, erythropoietic/X-linked protoporphyria-EPP/XLP) or hepatic (acute hepatic porphyrias-AHPs, porphyria cutanea tarda-PCT), according to the site of organ dysfunction deemed to be responsible for the disease. In terms of total heme production, the liver accounts for the second major heme-synthesizing organ, after the bone marrow. In fact, heme is necessary as a prosthetic group in countless biologic functions, to which hepatic contribution is essential. Furthermore, the pathway of heme biosynthesis is inscribed into a network of fundamental metabolic reactions largely occurring in hepatocytes. Independent of their classification, all porphyrias share some degree of involvement of the liver, either in the pathogenesis, clinical manifestations, or as a preferential target of damage. Crucially, even those types of porphyrias that have been classically defined as erythropoietic do present a hepatic involvement, which can lead to poor clinical outcomes if neglected. Therefore, hepatologists should consider porphyrias as a differential diagnosis for otherwise unexplained presentations of liver disease. At the same time, a multidisciplinary team dealing with the diagnostic workup and clinical management of all types of porphyrias must include an expert in liver diseases. In this review, we aimed to recapitulate the main aspects of liver involvement in porphyrias, while also providing practical tools to recognize and manage these conditions from the hepatologist's perspective.
Humans↗
Hepatic porphyrias. Current concepts.
Acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria are hepatic porphyrias due to enzyme defects that are inherited as autosomal dominants. Porphyria cutanea tarda is considered an acquired disorder. Similar drugs or circumstances are precipitants of acute attacks in all three inherited hepatic porphyrias. The respective biochemical abnormalities are identifiable by simple, readily available laboratory tests. Management of patients with any of the inherited hepatic porphyrias is directed primarily toward prevention of attacks through avoidance of precipitants and through a diet high in carbohydrate. Therapy for porphyria cutanea tarda includes interdiction of alcohol use and repeated phlebotomy.
5-Aminolevulinate Synthetase↗
Porphyria cutanea tarda associated with lymphoma.
Three patients with porphyria cutanea tarda and lymphoma were seen at the Mayo Clinic. In one patient, the signs and symptoms of porphyria cutanea tarda and lymphoma occurred simultaneously, whereas in the other two, the porphyria was seen before the lymphoma occurred, three years before in one and one and a half years before in the other. Involvement of liver or marrow was not related to the development of porphyria cutanea tarda in any of the 3 patients. The porphyria cutanea tarda was not eased by radiotherapy or chemotherapy of the lymphoma, although it was probably less symptomatic after the patients were treated. While a relationship between porphyria cutanea tarda and lymphoma is speculative, confirmation will require a closer scrutiny of patients with these two diseases.
Aged↗
New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation.
In two young patients with acute hepatic porphyria syndrome and persisting paralyses, which increased in intensity during intermittent occurring crisis, the activity of erythrocyte porphobilinogen synthase (delta-aminolevulinic acid dehydratase) was found to be considerably diminished, below 1% of the value of normal control persons. In contrast, the activity of uroporphyrinogen synthase was normal. Both patients have been excreting high quantities of delta-aminolevulinic acid and porphyrins in urine for years. Lead intoxication has definitively been excluded. Since the relatives also show lower activities in porphobilinogen synthase, the disease of these two patients is probably a new enzymatic type of inherited acute hepatic porphyria, the excretion profile of which is qualitatively completely different from those of the known acute porphyrias. The discovery of this porphyria confirms the theory of overlapping transition in the biochemical and clinical symptoms and analogies among acute hepatic porphyrias.
Acute Disease↗
Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.
There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of delta-aminolevulinic acid synthetase [delta-aminolevulinate synthase; succinyl--CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of delta-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of delta-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum delta-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement.
5-Aminolevulinate Synthetase↗
delta-Aminolevulinic acid: influences on synaptic GABA receptor binding may explain CNS symptoms of porphyria.
Symptoms of acute porphyria have been attributed to effects of delta-aminolevulinic acid (ALA). We report that ALA selectively competes for the binding of tritiated gamma-aminobutyric acid ([3H]GABA) associated with synaptic GABA receptors in central nervous system membranes. Concentrations of ALA that inhibit GABA receptor binding are consistent with levels of ALA thought to exist in the central nervous system of porphyric patients. Some of the symptoms of acute porphyria resemble those elicited by muscimol, a potent GABA agonist drug. Barbiturates, which exacerbate porphyric symptoms, are potent facilitators of the synaptic actions of GABA. The results suggest that some symptoms of acute porphyria might be attributable to a mimicking by ALA of GABA at its central nervous system receptor sites.
Aminolevulinic Acid↗
Increased sensitivity to lead -- animal model: feline porphyria.
Individuals with the genetically inherited condition of latent porphyria have been previously hypothesized (1) as being a potential high risk group to elevated lead exposure. More specifically, persons with either clinical symptoms of porphyria or the latent form who also are exposed to excessive lead may have their clinical symptoms exacerbated or possibly induced prematurely, respectively. This paper presents evidence that an animal model (i.e., domestic cats with congenital porphyria) may facilitate the testing of the previous hypothesis.
Animals↗
Neuropathy in latent hereditary hepatic porphyria.
Peripheral nerve conduction velocoties were measured in 20 patients with acute intermittent porphyria and five with variegate porphyria and in 25 controls matched for age and sex. None of the porphyric patients had acute symptoms on examination, and nine had never had symptoms. Compared with the controls, patients had a significantly slower conduction velocity of the slower motor fibres of the ulnar nerve (P less than 0-001) and a slower sensory conduction velocity of the ulnar and median nerves (P less than 0-05). There was no significant difference between the patients and controls in the maximum motor conductionvelocity of the median, ulnar, deep peroneal, or posterior tibial nerves. Slight peripheral neuropathy seems to be associated with latent hereditary hepatic porphyria, even in patients who have never had symptoms.
Adolescent↗
[Hepatic porphyria].
Porphyria is making increasing demands on the attention of clinicians and research worker. An account is given of hepatic forms, since these have recently come into prominence on account of recent advances in the understanding of their metabolic, diagnostic and therapeutic aspects. A description of the physiopathology of porphyrin metabolism is followed by an examination of the incidence, genetic features, aetiology, pathogenesis, pathological anatomy, symptomatology, diagnosis, prognosis, and treatment of each form. Particular attention is devoted to intermittent acute and cutanea tarda porphyria, since these are more commonly encountered in practice. Personal experience gathered in a large series of cases of cutanea tarda porphyria is presented.
Aminolevulinic Acid↗
Porphyria cutanea tarda: clinical and laboratory features.
Eleven patients with porphyria cutanea tarda were studied. Biochemical confirmation of the clinical diagnosis required only determination of the total urine porphyrin concentration in a sample of urine voided on rising in the morning. The patients were divided for convenience of discussion into four groups differing in age, sex and etiologic factors. Of the six patients in whom a liver biopsy was done one was shown to have micronodular cirrhosis. Except for a modest elevation in the serum glutamic oxaloacetic transaminase values when the patients were first seen, no evidence was found for liver disease apart from the presence of porphyria cutanea tarda. One patient recovered solely by abstaining from alcohol consumption. Five patients underwent phlebotomy; their iron stores had been found to be between 2 and 3 g. Decreasing urine porphyrin values correlated well with decreasing serum ferritin values during the course of phlebotomy. Porphyria cutanea tarda, which is due to a deficiency of uroporphyrinogen decarboxylase, is manifested in association with alcohol abuse, estrogen therapy, exposure to chlorinated hydrocarbons or increased tissue iron stores, or a combination of these factors. Although relatively uncommon, this condition raises important and unresolved issues regarding the hepatotoxicity of alcohol, estrogens, chlorinated hydrocarbons and iron.
Adult↗
Lack of linkage between acute intermittent porphyria and the A and B loci of the HLA system.
Forty-six members of a family known to have Porphyria were studied. As the disease is often latent clinically, erythrocyte uroporphyrinogen I synthetase activity was determined to classify the subjects as being healthy or carriers. HLA--A, B, C, Bf, GLO antigens were determined. No linkage between acute intermittent Porphyria and the HLA system was noted in this family.
Acute Disease↗
Reduced ferrochelatase activity in fibroblasts from patients with porphyria variegata.
Ferrochelatase deficiency has been shown in both porphyria variegata (PV) and erythropoietic protoporphyria (EPP). It has been suggested that in PV there is a decrease in the enzyme, whereas in EPP the enzyme is unstable. In the present study ferrochelatase activity was measured in skin fibroblasts from three patients with PV and three normal subjects. The enzymatic activity in the patients with PV (17.5 +/- 4.5 pmoles heme formed per 10(7) fibroblasts per hour) was 50% of that of the control group (31.0 +/- 3.2 pmoles heme formed per 10(7) fibroblasts per hour). This supports the contention that the enzyme is deficient in PV and that an inactive ferrochelatase is the primary deficiency in this type of porphyria.
Fibroblasts↗
Enzymatic defects of hereditary porphyrias: an explanation of dominance at the molecular level.
In four of the five autosomal dominant porphyrias four different partial enzymatic defects of the porphyrin biosynthetic pathway have been discovered in the last few years. With the exception of protoporphyria, the residual enzymatic activity in carriers of these defects is approximately equal to 50% of that found in controls. In each case the pattern of excretion of porphyrin and/or porphyrin precursors reflects the stie of the partial metabolic block. There are indications, at least in intermittent acute porphyria, that the degree of penetrance of the disorder varies according to the level of phenotypic expression, being highest for the enzyme deficiency, lower for the excretion of precursors and lowest for the clinical symptoms. It is proposed that environmental factors, and probably also gene interaction, are the cause of the different degrees of penetrance.
5-Aminolevulinate Synthetase↗
Study of erythrocyte delta-aminolevulinic acid dehydratase activity in porphyria cutanea tarda.
The erythrocyte delta-aminolevulinic acid dehydratase activity was studied in porphyria cutanea tarda patients, compared to healthy controls, in an attempt to resolve the contradictions in the relevant literature data. In an in vitro experimental system, a study was also made of how the erythrocyte delta-aminolevulinic acid dehydratase activity varies on the action of the activators -SH and Zn2+. It was found that, compared to the healthy controls, the erythrocyte delta-aminolevulinic acid dehydratase activity of porphyria cutanea tarda patients is significantly decreased, but it is restored to the original activity level on the addition of -SH and Zn2+. Since there is a general -SH requirement of delta-aminolevulinic acid dehydratase, the most obvious explanation for the decrease of the activity in the case of the patients is the shift of the natural redox systems of the erythrocytes, and the decrease of the reduced glutathione/oxidized glutathione ratio.
Adult↗
Aucte intermittent porphyria and epilepsy.
A 14-year-old boy had suffered from intermittent acute hepatic porphyria, myoclonic convulsions and mental retardation (Lennox-Gastaut syndrome). The porphyria was treated by stopping the administration of phenobarbitone and phenytoin. Sodium valproate at a dose of 70 mg/kg per day lessened the severity and frequency of convulsive crises.
Acute Disease↗
Studies on the mechanism of the changes in serum and liver gamma-glutamyl transpeptidase activity. II. Experimental hexachlorobenzene porphyria in rabbits.
The mechanism responsible for the changes in serum and liver gamma-glutamyl transpeptidase (gamma-GT) activity was studied in a model of experimental hexachlorobenzene porphyria in rabbits. Porphyria followed the administration of hexachlorobenzene in doses of 280 mumol - kg-1 body weight, which were given daily through a gastric tube over a 20-day period. Serum gamma-GT activity and the activities of the lysosomal enzymes beta-N-acetylglucosaminidase and alpha-mannosidase were increased, whereas L-aspartate: 2-oxoglutarate aminotransferase and L-alanine: 2-oxoglutarate aminotransferase and L-alanine: 2-oxoglutarate aminotransferase remained unaltered. There was a considerable increase in liver microsomal protein, gamma-GT, cytochrome P-450, anilinehydroxylase, aminopyrine-demethylase and delta-aminolevulinic acid synthase. In the liver gamma-GT was detected in the microsomes as well as in the cytoplasm where enzymatic activity was higher. The high correlation coefficient between liver gamma-GT, cytochrome P-450 and delta-aminolevulinic acid synthase witnesses a hexachlorobenzene-induced gamma-GT formation in the liver. A statistically significant correlation between serum and liver gamma-GT activity was also found. These data strongly suggest that the increase in serum gamma-GT activity may result from the induction of the enzyme in the liver.
Acetylglucosaminidase↗