Porphyria caused by genetic or acquired disorders enzyme in the biosynthesis of heme. Through these disorders there is an accumulation of precursor molecules of heme, which toxicity is caused. Porphyria are defined by the specific enzyme defects. There are two main clinical manifestations: Neuro Visceral disorders (acute porphyria) and cutaneous photosensitivity (cutaneous porphyria).
Heme, an iron-containing pigment, is an essential cofactor of numerous hemoproteins. require virtually all cells of the human body and synthesize heme. Most of heme but synthesized (by erythroblasts and reticulocytes) in the bone marrow and incorporated into hemoglobin. The liver is the second most active site of the heme synthesis, most of which is incorporated into the cytochrome P-450 enzymes. The heme biosynthesis requires eight enzymes (see Table: substrates and enzymes of the heme biosynthesis and the problems associated with their lack of diseases). These enzymes produce and transform molecular species, the porphyrins are called (and their precursors); an accumulation of these substances causes the clinical manifestations of porphyria.
Porphyria caused by genetic or acquired disorders enzyme in the biosynthesis of heme. Through these disorders there is an accumulation of precursor molecules of heme, which toxicity is caused. Porphyria are defined by the specific enzyme defects. There are two main clinical manifestations: Neuro Visceral disorders (acute porphyria) and cutaneous photosensitivity (cutaneous porphyria). Heme, an iron-containing pigment, is an essential cofactor of numerous hemoproteins. require virtually all cells of the human body and synthesize heme. Most of heme but synthesized (by erythroblasts and reticulocytes) in the bone marrow and incorporated into hemoglobin. The liver is the second most active site of the heme synthesis, most of which is incorporated into the cytochrome P-450 enzymes. The heme biosynthesis requires eight enzymes (see Table: substrates and enzymes of the heme biosynthesis and the problems associated with their lack of diseases). These enzymes produce and transform molecular species, the porphyrins are called (and their precursors); an accumulation of these substances causes the clinical manifestations of porphyria. Etiology With the exception of sporadic type Porphyria cutanea tarda (PCT), the porphyrias hereditary diseases. An autosomal dominant (AD) inheritance is most common. The AD porphyria (h, i. E. Two separate heterozygous mutations one in each allele of the same gene in the same patient) homozygous or heterozygous mixed states may be incompatible with the conditions for the survival of what caused the fetal death in general. The penetrance of the disease varies in heterozygotes; therefore, the clinical expression of the disease is less common than the genetic prevalence. The 2 common porphyria, PCT and acute intermittent porphyria (AIP) are, AD (20% of the PCT is AD). The prevalence of PCT is about 1 in 10,000. The prevalence of the causative mutation for AIP is about 1 in 1,500; However, since penetrance is low, the prevalence of clinical disease is also at about 1 in 10,000. The prevalence of PCT and the AIP varies greatly between regions and ethnic groups. The autosomal recessive porphyria, causing only homozygous or heterozygous mixed states the disease. Erythropoietic Protoporphyrie, the third most common porphyria is an autosomal recessive trait. An X-linked inheritance occurs at one of porphyria: X-linked Protoporphyrie. Substrates and enzymes of the heme biosynthesis and the data associated with the deficiency diseases substrate / enzyme * porphyria neurovisceral symptoms Cutaneous symptoms inheritance glycine + succinyl-CoA erythroblast specific ?-aminolevulinic acid synthase-2 (ALAS 2) X-linked protoporphyria (due of increased enzyme activity) No phenotypic similarity with EPP X-linked ?-aminolevulinic acid ?-aminolevulinic acid dehydratase (ALAD) ALAD-deficient porphyria Yes No Autosomal recessive PBG PBG deaminase acute intermittent porphyria Yes No Autosomal dominant hydroxymethylbilane Uroporphyrinogen III Kosynthase Congenital erythropoietic porphyria No severity, mutilating skin disease Autosomal recessive Uroporphyrinogen III Uroporphyrinogen decarboxylase porphyria cutanea tarda No Fragile skin, blisters Two versions: Autosomal dominant (20-25% of cases) without known genetic correlate (sporadically, 75-80%) Hepatoerythropoetische porphyria No Severe blistering Autosomal recessive Koproporphyrinogen III Koproporphyrinogen oxidase Hereditary coproporphyria Yes Fragile skin, blisters Autosomal dominant protoporphyrinogen IX protoporphyrinogen oxidase porphyria variegata Yes fragile skin, blisters Autosomal dominant protoporphyrin IX Ferrochelatase Erythropoietic Protoporphyrie (EPP) No, except in patients with severe hepatobiliary pathology skin pain, lichenification and other minor changes the skin, but no blisters Autosomal recessive Heme (final product in various heme proteins built-in) – – – – * Listed are successive intermediates in the biosynthesis of heme, starting with glycine and succinyl-CoA and ending with heme. The lack of an enzyme causes the buildup of precursor compounds. X-linked Protoporphyrie result of gain-of-function mutations that increase the activity of ALAS 2, resulting in an accumulation of protoporphyrin Decreased activity of ALAS 2 causes sideroblastic. Pathophysiology porphyria caused due to a defect of the last seven enzymes of the heme biosynthesis or by increased activity of the first enzyme in the biosynthesis, ALA-synthase 2 (ALAS 2). (A defect of ALAS 2 rather causes a sideroblastic anemia, as a porphyria.) Individual genes encode each enzyme; each of the various possible mutations may modify the content and / or activity of the enzyme which is encoded by this gene. If an enzyme of the heme biosynthetic disturbed or occurs only with lack of activity may be the substrate, and any other precursor product of heme, which was usually changed by this enzyme, in the bone marrow, liver, skin or other tissues accumulate and have toxic effects. The precursor stages may have excessive levels in the blood and are excreted in the urine, bile or stool. Although porphyria are very clearly defined by the type of enzyme disorder, a classification by major clinical manifestations (phenotypes) is often useful. Porphyria are normally subdivided into two groups: acute Kutan Acute porphyria show up by intermittent bouts of abdominal, psychological and neurological symptoms. They are typically caused by drugs, cyclical hormone activity in young women and other exogenous factors. Cutaneous porphyria more likely to cause continuous or intermittent symptoms, including cutaneous photosensitivity counts. Some acute porphyria (hereditary coproporphyria, porphyria variegata) can also show a cutaneous manifestation. Due to the different penetrance of heterozygous porphyrias the clinical incidence of the disease is less common than their genetic prevalence (see Table: The main features of the two most common porphyria). Discoloration of urine (red or reddish-brown) may occur in the symptomatic phase of all porphyria, except for erythropoietic Protoporphyrie (EPP) and ALAD deficiency porphyria. The discoloration caused by oxidation of the porphyrins, the Porphyrinvorläufers porphobilinogen (PBG), or both. Occasionally, the discoloration, developed only after the urine was suspended for about 30 minutes and the light was so time for non-enzymatic oxidation. In acute porphyria, except for ALAD deficiency porphyry, a have three heterozygotes (more common in women than men) during the latent phase, an increased excretion of PBG in the urine (and urine discoloration). The main features of the two most common porphyria porphyria Occurring symptoms Aggravating factors The most important screening tests * Treatment acute intermittent porphyria neuro-visceral medications (intermittent, acute) (mainly cytochrome P-450 inducers) fasting alcohol consumption Organic solvents infections Stress PBG in urine glucose heme porphyria cutanea tarda Blistering skin lesions (chronic) alcohol iron estrogens Hepatitis C virus (HCV) Halogenated hydrocarbons porphyrins in urine or plasma phlebotomy Low dose chloroquine or hydroxychloroquine * In the symptomatic phase. PBG = porphobilinogen. Diagnostic blood or urine tests, patients having symptoms of porphyria, be by means of tests on blood or urine or the porphyrins Porphyrinvorstufen PBG and ALA (see Table: Screening for porphyria) was investigated. Pathological values ??of these screening tests be clarified by further investigations. Asymptomatic patients, including persons in whom it is suspected that they are carriers of a genetic defect, or patient between two seizures are quite similar evaluated. Nevertheless, the tests are less sensitive in these circumstances; the measurement of the enzyme activity in erythrocytes and leukocytes shows a considerably higher sensitivity here. Genetic analysis is very accurate and should preferably be used within families, when the mutation is known. Prenatal tests (including amniocentesis or chorionic villus sampling) are possible but rarely indicated. Screening with porphyria tests (if the results of the screening test are clearly abnormal) ALA and PBG in the urine (quantitatively in patients with acute neuro-visceral symptoms in patients with photosensitivity screening process PBG in the urine (semiquantitative, random urine sample) porphyrins in plasma * Confirmation ) faecal and urinary porphyrins porphobilinogen deaminase in erythrocytes porphyrins in plasma * porphyrins in the erythrocytes ALA, Porphob ilinogen deaminase and porphyrins (quantitative) in the urine porphyrins in stool porphyrins in plasma * * The preferred method is the direct fluorescent spectrophotometry. Porphyrins in urine and faeces are only fractionally when the sum is increased. The results are corrected in the urine after the creatinine level. ALA = ?-aminolevulinic acid; PBG = porphobilinogen. Secondary porphyrinuria Several diseases that are independent of porphyria can include increased secretion of porphyrins in the urine; This phenomenon is described as secondary porphyrinuria. Hematological diseases, liver diseases and toxins (eg. As alcohol, benzene, lead) can cause increased urinary coproporphyrin precipitates. Increased coproporphyrin excretion in urine can occur with any liver disease because the bile is one of the ways of porphyrin excretion. Uroporphyrin may be increased in patients with liver disease. Protoporphyrin is not excreted in the urine because it is not water soluble. Some patients have abdominal pain and neurological symptoms that resemble a acute porphyria. Renal ALA and PBG are not increased in these diseases generally and normal levels helps to distinguish between secondary porphyrinuria and acute porphyria. However, some patients may have with lead poisoning increased ALA content in the urine. In such patients, the lead content should be determined in the urine. If ALA and PBG are increased normal or only slightly in the urine, the measurement of total porphyrins in the urine and a high-performance liquid chromatography of these porphyrins useful in the differential diagnosis of syndromes of acute porphyria are.