Porphyrias are rare, inherited defects in heme synthesis, which result in an accumulation and increased excretion of porphyrins. The mutation that cause the porphyria are heterogeneous, nearly every family that affected has its own mutation. Porphyria refers to the purple color casued ny pigment like porphyrins in the urine of some patient in defect in heme synthesis. These disorders are classified as hepatic or erythropoetic depend on the primary site of overproduction and accumulation of the porphyrin precursors. The major manifestations of the hepatic porphyrias are neurologic, including neuropathic abdominal pain, neuropathy, and mental disturbances, whereas the erythropoietic porphyrias characteristically cause cutaneous photosensitivity. Cutaneous sensitivity to sunlight is due to long-wave ultraviolet light excitation of excess porphyrins in the skin, leading to cell damage, scarring, and deformation.
Porphyrias are normally some kind of group of rare disorders passed down through families which means that it is genetic, in which an important part of hemoglobin which called heme, is not made properly. Heme is also found in myoglobin, which is a protein that found in certain muscles. Our body normally makes heme in a multi-step process. Porphyrins are made during several steps of this process. In this process or biosynthetic pathway there are several enzymes that are required to process this pathway. When there is a deficiency of any of these particular enzymes, which will lead to a serious problem which can lead to life threatening. Normally the patient will have fewer amounts in part and excess amount in another part. Patients with poryphyria have has a deficiency of certain enzymes needed for this process. This causes abnormal amounts of porphyrins to build up in the body. The biosynthesis of porphyrins is the formation of d anolevulinic acid (dALA) which is the first compound in the porphyrins synthesis pathway, but the reaction of the amino acid glycine and succinyl CoA from the TCA cycle. There are two molecules that combine to give porphybilinogen which contain a pyrole ring.
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This hepatic porphyria is an autosomal dominant condition resulting from the half-normal level of this enzyme activity. The disease is widely spread but is especially more common in Scandinavia and Great Britain. These diseases are characterized of gastrointestinal, neurological and psychological, and cardiovascular symptoms. The enzyme deficiency can be demonstrated in most heterozygous individuals, but clinical expression is highly variable. Symptom of acute intermittent porphyria are often precipitated by administration of drugs such as barbiturates and ethanol, which allow to induce the heme containing cytochorme P450 microsomal drugs oxidation system.. This can decrease the amount of availability heme, which in turn promotes the increase synthesis of ALA synthase. Activation of the disease is related to environmental or hormonal factors, such as drugs, diet, and steroid hormones, which can precipitate the manifestations.
Any type attacks can be prevented by avoiding known precipitating factors.
To illustrate this pathway, there should be an explanation for each step the biosyntehisis of heme is occurs in the liver, which synthesizes a large number of hem and protein. Glycine and succinyl Coa dondensed to form D-Ainolevulinic acid, this reaction is catalyzed by ALA synthase, which is the rate limiting enzyme in porphyrin and he biosynthesis. ALA synthase is what makes the reaction moves forward. In humans, transcription of ALA synthase is tightly controlled by the presence of FeHYPERLINK "http://www.ask.com/wiki/Iron?qsrc=3044"2+- binding element, to prevent these type of accumulation of the porphyrin intermediates when there is no iron. Our body has two form of ALA synthase in the body. One form is normally expressed in red blood cell precursor cells, whereas the other is expressed throughout the body. The red blood cell form is coded by some type of gen which is on the chromosome X, whereas the other one is coded by the gene on the chromosomes. When there is a deficiency of this enzyme, there will be an accumulation in this enzyme. Porphobilinogen form the hydroxymethyl bilane which catalyzed by the enzyme of porphobilinogen deaminase. Deficiency of this enzyme there will be an accumulation of porphobilinogen which will cause the acute porphyria. This results in an excessive production of the heme precursor's aminolevulinic acid and porphobilinogen. Most individuals remain clinically latent until a precipitating factor triggers an acute attack. Porphobilinogen deaminase is an enzyme used in heme synthesis.
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Most of these heterozygotes remain clinically asymptomatic (latent) unless exposed to factors that increase the production of porphyrins. The disease can de disabling but is rarely fatal. Abdominal pain, the most common symptom, is usually poorly and steady localized maybe due to cramps, abdominal distention and decreased bowel sounds are all common. These patients can also have tachycardia, hypertension, mental problem, restlessness, tremors; they tend to sweat a lot. These patients may also present with peripheral neuropathy which is normally due to axonal degeneration and primarily affects motor neurons. In most cases neuropathy does not occur with all acute attacks.
Some mental symptoms such as anxiety, insomnia, depression, disorientation, hallucinations, and paranoia can occur in acute attacks. Seizures can be due to neurologic effects or to hyponatremia. The treatment for seizures is very difficult because virtually all antiseizure drugs except bromides may exacerbate acute intermittent porphyria. Hyponatremia results from the hypothalamic involvement and inappropriate vasopressin secretion or from electrolyte depletion due to vomiting, diarrhea, poor intake, or excess renal sodium loss. Persistent hypertension and impaired renal function may occur. When an attack resolves, abdominal painmay disappear within hours, and paresis begins to improve within days and may continue to improve over several years
ALA1 and PBG2 levels are increased in plasma and urine during acute attacks. Urinary Porphyria bilinogen excretion is usually 220 to 880 umol/d (50 to 200 mg/d) the normal is 0 to 18 umol/d and the urinary for ALA excretion is 150 to 760 umol/d (20 to 100 mg/d) the normal is around 8 to 53 umol/d The excretion of these compounds generally decreases with clinical improvement, particularly after hematin infusions (see below). A normal urinary PBG level effectively excludes AIP as a cause for current symptoms. Fecal porphyrins are usually normal. The test that they do is what is called the Ehrlich Aldehyde Test which is sued to confirm a diagnosis of an acute intermittent porphyria. When they do the test, if a pink color is formed that is indicates a raised in urine concentration of either porphobilinogen or urobilonogen. In cases of raised porphobilinogen, as in acute intermittent porphyria, the pink precipitate is observed to be insoluble in chloroform the renal insufficiency and coagulopathy. Specific symptoms should be treated during an attack.
phenothiazines are useful for nausea, vomiting, anxiety, and restlessness. Chloralhydrate can be given for insomnia, and benzodiazepines are probably safe in low doses, if a minor tranquilizer is required. Although intravenous glucose such at 300
g/d can be effective in acute attacks of porphyria. However, intravenous heme is more effective than glucose in reducing porphyrin precursor excretion and probably leads to more rapid recovery. The response to heme therapy is reduced if delayed. Therefore, 3 to 4 mg of heme, in the form of hematin, heme albumin, or heme arginate may be infused daily for 4 days beginning as soon as possible after onset of an attack. The rate of recovery from an acute attack depends on the degree of neuronal damage and may be rapid as1 to 2 days with prompt therapy. Recovery from severe motor neuropathy may require months or years. Multiple inciting factors may contribute to a symptomatic episode.
A 14 year old male presented with one week history of episodic severe abdominal pain associated with vomiting 3 to 4 times a day and dark reddish urine. He developed rapidly progressive weakness in all the four limbs for 2 days prior to hospitalization. In the past, he had 2 episodes of similar abdominal pain along with altered sensorium and generalised epileptic fits but without any weakness of limbs.
Examination revealed a fully conscious, thin built patient with normal pulse and blood pressure. Abdominal examination did not reveal any abnormality. Neurological checkup showed features of flaccid quadriparesis with bilateral foot drop. There was no sensory impairment.
Laboratory investigations showed the TLC of 11,300/cmm with a DLC of P-77%, L-19%, E-3% and M-1%. His hemoglobin was 13.5 gm% and ESR, 27 mm in the 1st hour. Urine was strongly positive for PBG. Urine samples of his parents and sisters were negative for this pigment. CSF was normal. NCV showed features of diffuse neuropathy.He were treated with chlorpromazine, 50 mg three times a day together with other general supportive and symptomatic measures. He had remarkable improvement within a week's time. At the time of discharge from the hospital, the patient was given a card regarding the diagnosis and list of common drugs known to precipitate the acute attacks of porphyria.
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