Frequency of low erythrocyte porphobilinogen deaminase activity in Finland.

The frequency of low erythrocyte porphobilinogen deaminase (PBGD) activity was investigated in 2234 blood donors and in 30 patients with acute intermittent porphyria. The mean enzyme activities (+/- SD) were 3.38 +/- 0.58 U and 1.82 +/- 0.41 U, respectively. Eighteen blood donors without any history of symptoms of porphyria or haematological disease had low PBGD activity (less than 2.20 U), and they were studied further. All of them also had subnormal concentrations of the erythrocyte enzyme protein, as determined by an immunological method. Lymphocyte PBGD activity was within the normal range, but this parameter does exhibit a wide overlap between normal and porphyric values. Urinary excretion of porphobilinogen was moderately increased in two of the blood donors. In four of the 18 families of the blood donors with low PBGD activity several first-degree relatives had low erythrocyte enzyme activity, consistent with a dominant mode of inheritance. The 5-aminolaevulinic acid loading-test was normal in the blood donors with familial occurrence of low erythrocyte PBGD. It is concluded that inherited defects in erythrocyte PBGD occurred among Finnish blood donors with a frequency of about 1 in 500. The defects may be identical with those in acute intermittent porphyria (AIP), but other mechanisms are also possible, e.g. a mutation in the erythroid-specific part of the PBGD gene.     

Erythrocyte porphobilinogen deaminase activity in liver disease

The activities of erythrocyte porphobilinogen deaminase were studied in patients with various liver diseases and in control groups. The lowest enzyme activities were found in patients with acute intermittent porphyria, and the highest ones in those with increased hemopoietic activity. Patients with liver cirrhosis or chronic active hepatitis had porphobilinogen deaminase activities that were significantly higher than in normal subjects and did not depend on disease activity. In patients with acute hepatitis, porphobilinogen deaminase activities varied depending on the phase of disease, being normal at onset and after 3-4 mo, and elevated to the values observed in chronic liver disease between 2 and 4 wk of hospitalization. The differences in porphobilinogen deaminase activities between patients with liver disease and controls did not relate to red cell age as determined by density gradient centrifugation. Therefore, although the mechanism responsible for the increase in porphobilinogen deaminase activities in liver disease is not clear, the results of this study suggest that it is independent of the presence of immature red cells in the circulation.     

Porphyrien

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria and Doss porphyria belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological and cardiovascular symptoms. The diagnosis is based on a tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like Porphyria cutanea tarda, Erythropoietic protoporphyria and Congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin up to severe liver damage. The location of the deficient enzyme within the heme biosynthesic pathway determines the pattern of the accumulated porphyrins. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.     

Porphyrias

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria and Doss porphyria belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological and cardiovascular symptoms. The diagnosis is based on a tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like Porphyria cutanea tarda, Erythropoietic protoporphyria and Congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin up to severe liver damage. The location of the deficient enzyme within the heme biosynthesic pathway determines the pattern of the accumulated porphyrins. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.     

Variegate porphyria

In temperate and cold climates the most usual presenting symptom of variegate porphyria is an acute porphyric attack, indistinguishable from that seen in acute intermittent porphyria. Increased fragility of the skin in sun-exposed areas occurs in only half of such patients, and even then is usually mild and easily overlooked. The diagnosis depends on fecal excretion of porphyrins, which is greatly increased in variegate porphyria and consists predominantly of protoporphyrin. Urinary excretion of porphobilinogen and delta-aminolevulinic acid increases only during acute attacks. There are reasons for thinking that variegate porphyria is commoner than hitherto supposed. During an acute attack a patient without skin symptoms may well be misdiagnosed as having acute intermittent porphyria, because of identical symptoms and excretion of porphobilinogen in the urine. Thus, for a correct diagnosis, every patient presenting with symptoms of acute porphyria requires a fecal analysis.     

Heme Biosynthesis in Intermittent Acute Porphyria: Decreased Hepatic Conversion of Porphobilinogen to Porphyrins and Increased Delta Aminolevulinic Acid Synthetase Activity

Hepatic conversion of porphobilinogen to porphyrins was less than 50% of control levels in human subjects with the genetic disease, intermittent acute porphyria. This relative block in heme biosynthesis may be relevant to a concomitant 6- to 10-fold elevation in delta-aminolevulinic acid synthetase activity, since this first and rate-controlling enzyme in the biosynthetic pathway is subject to negative feedback regulation by the end product, heme. A micro-radio-chemical assay of delta-aminolevulinic acid synthetase, and some of its applications, are described.     

Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria

Summary The molecular abnormalities responsible for acute intermittent porphyria were investigated in both parents of a girl who was retrospectively diagnosed as having a homozygous form of the disease. The mutations in the parents are different from each other and both of them correspond to previously identified G to A changes in the coding part of the porphobilinogen deaminase mRNA. These point mutations lead to the presence of a catalytically-defective but immunologically-reactive enzyme. Our results support the conclusion that the propositus girl may represent the first case of compound heterozygosity for acute intermittent porphyria alleles.     

An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity

Four forms of porphyria may present clinically with the acute attack, an episodic, severe, and potentially life-threatening manifestation characterized by abdominal and neurologic symptoms. We describe our experience with 112 consecutive attacks observed and treated in 25 patients with the 2 most common forms of acute porphyria in Cape Town, South Africa; 25 attacks in 10 patients with variegate porphyria and 87 attacks in 14 patients with acute intermittent porphyria. The remaining patient experienced more than 100 sequential, severe, and poorly remitting attacks, which are not included in our analysis. In our population, the relative risk of an acute attack in acute intermittent porphyria compared with that in variegate porphyria was 14.3 (confidence intervals, 6.3-32.7). Patients with variegate porphyria were significantly older (median age at first attack, 30 yr) than those with acute intermittent porphyria (median age at first attack, 23.5 yr; p < 0.0001), and demonstrated an equal sex ratio, whereas the male:female ratio in acute intermittent porphyria was 2:12 (p < 0.0001). There was a significant difference in the incidence of factors precipitating the acute attack. Drug exposure was a frequent precipitant of the acute attack in variegate porphyria, whereas hormonal factors were more important in acute intermittent porphyria (p < 0.00001). Patients with acute intermittent porphyria also showed a trend to earlier and more frequent recurrent acute attacks following the initial admission. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate requirement were all significantly higher in patients with acute intermittent porphyria. No significant difference in the frequency of serious complications or in outcome could be shown. We describe our experience with treatment with heme arginate, and provide evidence that heme arginate results in a prompt and statistically significant improvement in symptoms. The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment.     

Acute intermittent porphyria--diagnostic and treatment traps

Acute intermittent porphyria (AIP) is a rare metabolic disease defined by mutations coding the deaminaze enzyme of porphobilinogen (PBGD). Porphyrias are somewhat misdiagnosed as a consequence of light symptoms in patients. Acute forms of porphyria can be life-threatening, so a correct diagnosis and an accurate treatment are highly important. The authors presented the case of a 38-years-old patient admitted for persistent abdominal pain that previously presented two generalized convulsive seizures. The diagnosis of AIP was established by the raised concentration of urinary porphyrins. Despite treatment with carbohydrates and hemines, the clinical picture of the patient worsened, with tetraplegia and severe respiratory failure. The patient died seven weeks after the initial presentation of the disease.     

Tissue-specific splicing mutation in acute intermittent porphyria

An inherited deficiency of porphobilinogen deaminase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] in humans is responsible for the autosomal dominant disease acute intermittent porphyria. Different classes of mutations have been described at the protein level suggesting that this is a heterogeneous disease. It was previously demonstrated that porphobilinogen deaminase is encoded by two distinct mRNA species expressed in a tissue-specific manner. Analysis of the genomic sequences indicated that these two mRNAs are transcribed from two promoters and only differ in their first exon. The first mutation identified in the human porphobilinogen deaminase gene is a single-base substitution (G----A) in the canonical 5' splice donor site of intron 1. This mutation leads to a particular subtype of acute intermittent porphyria characterized by the restriction of the enzymatic defect to nonerythropoietic tissues. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offers another possibility of detecting asymptomatic carriers of the mutation in affected families.     

Porphyrien – was ist gesichert?

Porphyrias are caused by enzyme defects of heme biosynthesis. According to their clinical presentation and to each affected pathway, they are categorized into acute and non-acute as well as hepatic and erythropoietic porphyrias. Acute hepatic porphyrias, e.g. acute intermittent porphyria (AIP), porphyria variegata (VP), hereditary coproporphyria (HCP) and 5?aminolevulinic acid dehydratase-deficient porphyria (ALADP) are characterized by accumulation of the porphyrin precursors 5?aminolevulinic acid (ALA) and porphobilinogen (PBG) that correlate with severe abdominal, psychiatric, neurological or cardiovascular symptoms. Additionally, skin photosensitivity can occur in VP and less frequently, in HCP. Decisive for the diagnosis of acute hepatic porphyrias are a >4-fold elevated urinary excretion of ALA in ALADP and ALA and PBG in all other acute porphyrias. First-line treatment of an acute porphyria attack includes intensive care with pain management, sufficient caloric supply, strict avoidance of porphyrinogenic drugs and elimination of other triggering factors. Heme therapy is indispensable in case of developing neurological symptoms and clinical worsening despite first-line measures. Non-acute porphyrias, mainly porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP) and X?linked protoporphyria (XLP) display accumulation of porphyrins in the skin and/or liver resulting in photosensitivity up to possible liver damage. Patients with PCT benefit from iron depletion, low-dose chloroquine treatment and/or hepatitis C virus elimination. Afamelanotide is associated with better sunlight tolerance in patients with EPP and XLP. Moreover, innovative therapies that highly selectively address dysregulated steps of the heme biosynthetic pathway are currently under clinical trial.     

Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases.

We evaluated the prognosis of acute porphyria among 206 adult Finnish patients with acute intermittent porphyria (AIP) or variegate porphyria (VP). The series represents all known patients with these porphyrias in Finland. Of the 47 patients who had a total of 117 acute attacks during the period 1967-1989, 6 died during an attack and 21 attacks were associated with paresis; the frequency of severe attacks was significantly smaller than before 1967 (p = 0.00002). Most pareses and deaths occurred because of a delay in diagnosis and inappropriate treatment of porphyria. For those patients who were symptom-free at the time of diagnosis (1365 follow-up years), the risk of the first subsequent attack was significantly smaller than for those who had had an acute attack before the diagnosis of porphyria (1047 follow-up years, p = 0.005). In addition, milder symptoms of porphyria were more common among those who had had previous attacks than among those who had not (p less than 0.00001). In AIP the risk of attacks correlated with the excretion of porphobilinogen in the urine during remission among adults (p = 0.03); a low rate of excretion predicted freedom from acute attacks. A regular use of many precipitating drugs was never associated with symptoms of porphyria. Two percent of the surgical operations and 4% of the pregnancies were associated with acute attacks. Nearly one-third of the women had symptoms of porphyria associated with the menstrual cycle, but these seldom proceeded to an acute attack. Forty-six percent of the women had used sex-hormone preparations regularly; 2 of them (4.5%) experienced associated acute attacks. Patients with AIP or VP showed increased incidences of hepatocellular carcinoma, and probably also chronic renal failure and hypertension.     

Liver transplantation for acute intermittent porphyria:a viable treatment?

BACKGROUND:Acute intermittent porphyria (AIP) is the most common hepatic porphyria.Its clinical presentation includes severe disabling and life-threatening neurovisceral symptoms and acute psychiatric symptoms.These symptoms result from the overproduction and accumulation of porphyrin precursors,5-aminoleuvulinic acid (ALA) and porphobilinogen (PBG).The effect of medical treatment is transient and is not effective once irreversible neurological damage has occurred.Liver transplantation (LT) replaces hepatic...     

Porphyrias

Seven different porphyrias form a group of inherited metabolic disorders, each resulting from a partial deficiency of a specific enzyme in the haem biosynthesis pathway. Clinically, the three most important entities are an acute porphyric attack and acute and chronic skin symptoms. Porphyrias are rare and sometimes misdiagnosed, because various symptoms and signs mimic other diseases. Once porphyria is suspected, biochemical analyses easily detect porphyrins and their precursors from blood, urine, or faeces. Mutation screening can be done at the quiescent phase of the disease. Pathogenetic mechanisms and clinical manifestations differ in individual porphyrias and most of them require a specific treatment. Early diagnosis and information about precipitating factors can diminish mortality and prevent subsequent attacks among patients with acute porphyrias, so mutation screening is recommended for family members.     

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 (-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 -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 -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 -aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.     

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.     

Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors

A 7-year-old boy demonstrating hepatosplenomegaly, mild anaemia, mild mental retardation, yellow-brown teeth and dark red urine had excessively elevated levels of urinary delta-aminolevulinic acid, porphobilinogen and uroporphyrin. Furthermore hepta-, hexa-, penta- and copro(I)porphyrins were highly increased in urine. This pattern of porphyrin precursor and metabolite excretion is characteristic of acute intermittent porphyria. The decreased copro(III)/copro(I+III) ratio, normally not found in acute intermittent porphyria, is discussed. The porphobilinogen deaminase activity in red cells was decreased to 2-4%. Mutation analysis revealed a novel homozygous L81P mutation in exon 6 of the porphobilinogen deaminase gene. The father and mother, shown to be gene carriers of the same mutation, are asymptomatic and have normal urinary porphyrin precursor and metabolite excretion.     

Manifestation of acute intermittent porphyria in patients with chronic inflammatory bowel disease.

In a retrospective study covering 411 acute intermittent porphyria patients, four cases of a coincidence with Crohn's disease or ulcerative colitis were found. Their courses of disease confirmed that patients with chronic inflammatory bowel disease have a higher risk for acute porphyria manifestation. Both malnutrition (glycopenic induction) and sulphasalazine (drug-induced exacerbation) are known as triggering factors for acute porphyric states. Furthermore, diagnosis of acute intermittent porphyria tends to be much more difficult in such cases, as the acute phases of abdominal pain are likely to be associated with the enteral disease process. A delay of diagnosis and therapy of acute hepatic porphyria, however, may endanger the patient by pareses, which could be irreversible or even lethal. Therefore, whenever there is suspicion of a coinciding acute porphyria, urinary screening tests for porphyria should immediately be performed and, if a coinciding acute hepatic porphyria is diagnosed, porphyrogenic drugs like sulphasalazine should be avoided in treatment of chronic inflammatory bowel disease.     

A Microassay for Uroporphyrinogen I Synthase, One of Three Abnormal Enzyme Activities in Acute Intermittent Porphyria, and its Application to the Study of the Genetics of this Disease

A new spectrofluorometric assay is described for quantitating uroporphyrinogen I synthase (EC 4.3.1.8) activity in volumes of human blood as small as 2 mul. By this sensitive assay the inheritance of the enzyme's activity has been studied and the genetic defect for acute intermittent porphyria has been confirmed to be autosomal dominant in nature. There is a 3-fold range of uroporphyrinogen I synthase activity in erythrocytes in the normal population, with a mean V(max) +/- SD of 35.7 +/- 8.4 nmol of uroporphyrinogen I formed per ml of erythrocytes per hr, at 37 degrees . One-half this level of enzyme activity (18.0 +/- 5.0) is found in erythrocytes from patients with clinically manifest acute intermittent porphyria; and in erythrocytes from those of their relatives, including prepubertal children, who have the latent gene defect for the disease. The K(m) of erythrocyte enzyme of normal people is 12.3 +/- 3.9 muM, whereas the K(m) of the erythrocyte enzyme of patients with acute intermittent porphyria is 6.2 +/- 3.9 muM, as determined on whole blood lysates. Three enzymic changes have now been identified in patients with acute intermittent porphyria; a high level of delta-aminolevulinate synthase activity; a low level of uroporphyrinogen I synthase activity; and a deficiency of steroid Delta(4)-5alpha reductase activity.     

Molecular mechanisms of dominant expression in porphyria

Summary Summary:#Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified.