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A Guide To Porphyria

What are the causes of porphyria?
The porphyrin molecules are synthesized in the body from simple amino acids made up of carbon, nitrogen, hydrogen and oxygen. These amino acids interact under specific enzymatic control systems to form ALA then PBG and then on to the pyrolle rings. Each of the pyrolle rings has two side chains and the when the four pyrolle ring structures condense together to form a porphyrin, the combination of the eight side chains can form several variations called isomers. These isomers undergo further reactions where the side chains lose little segments containing carbon, hydrogen and oxygen and form an extensive variety of different molecules, all called porphyrins, but each has its own physico-chemical and biochemical properties. Most of these porphyrin molecules which are not involved in normal metabolic processes are produced in tiny amounts and are destroyed or eliminated as quickly as they are formed. These porphyrin degradation products are almost always water soluable and are excreted in the urine as uroporphyrins and in the stool as coproporphyrins. Only a very few of these isomers are clinicall important and essential for life. The one with the highest concentration is the porphyrin molecule incorporated in hemoglobin, but the porphyrins are also present in other systems such as the cytochrome P-450 group of enzymes which are essential for many other metabolic processes. As the red cells age they in turn are degraded and the porphyrin ring structures are ruptured to form a long chain molecule called bilirubin which gives the bile its yellow green colour. Most of the metabolic processes involving the porphyrins occur in the liver and in the bone marrow.

Each step in the synthesis, remodeling and destruction of the porphyrins is carried out by a sequence of chemical reactions under the control of enzymes. These enzymes are large protein molecules and are found in both the cytoplasm and the mitochondria of living cells. The rate of each specific chemical reaction is controlled by many factors, particularly the concentration and activity of the enzyme system. As a result they influence the concentrations of both the precursor and end products of the specific reaction. These enzymes are directly under the control of the DNA that is present in the chromosomes contained within the nucleus of the cells. The chromosomes have multiple condensations of coiled DNA which are called genes. The DNA in these genes makes RNA molecules, called messenger RNA which regulate the production of proteins including these enzyme systems.

In general, each individual gene influences several enzyme functions, and for the most part each enzyme system is under the control of multiple genes although the most of the specific enzymes involved in porphyrin synthesis seem to be encoded by single gene loci. . If the DNA composition of the gene is defective or abnormal, the metabolic functions that it controls probably will be defective as well. The 23 chromosomes themselves are paired, one set from the mother, and the other from the father with the result that apart from the x - y chromosome which is associated with the sex karyotype, all genes have duplicate representation in the chromosomes. If only one of the pair of genes is defective it can either be dominant to the other normal gene and alter the metabolic process, or be recessive to it in which case there will be no metabolic derangement. Rarely, both genes may have the same recessive characteristics, in which case the metabolic functions will be significantly altered. Although usually the gene is passed on intact via the ovum or sperm from parent to offspring, occasionally a change in the structure of the gene, called mutations can occur spontaneously and sometimes develop due to radiation, medications, etc. Many of the mutations of the individual genes involved in porphyria have been identified. Often the children of porphyric patients may be at risk of inheriting their parent's disease. At other times the disease may appear without any antecedent identifiable family involvement

Several problems can develop when the chemical reactions controlled by the specific enzymes are defective. If the enzyme process is slowed there may be a build up of potentially toxic precursors and if the chemical reaction is too fast the end products may accumulate in too high a concentration. Sometimes the abnormal enzyme systems change the direction of the reaction and produce abnormal metabolites. These precursors and end products can be retained within the cell cytoplasm where they may interfere with other metabolic processes or be sufficiently toxic to cause the death of the cells. Other water soluble compounds may be carried by the blood to other tissues such as the skin where they can absorb abnormal amounts of radiant energy and affect the body in a different way. Most compounds are simply excreted in the stool and urine in abnormal amounts without any clinical problem. In pregnancy, sometimes the abnormal compounds will not allow the developing fetus to survive. Other times the metabolic abnormality will not become apparent until well after puberty or even middle age. Frequently nothing will happen unless the enzyme abnormalities are changed or induced by other factors. Excesses of lead or iron overload syndromes, certain drugs such as barbiturates and sulfonamides along with infections such as the virus that causes hepatitis C can either cause porphyria or bring out latent cases.

What are the different types of porphyria?
For the most part, the various syndromes that are classified under the collective name of porphyria are differentiated from each other on the basis of a combination of clinical symptoms and abnormal biochemical findings in blood, urine & stool. On the basis of our current understanding of molecular biology this classification is somewhat unsatisfactory and illogical. Theoretically it would be preferable to classify the porphyrias on the basis of the specific gene or enzyme defects giving rise to the abnormal prophyrin concentrations causing these abnormal clinical and biochemical findings. Unfortunately, much of the gene and enzyme studies have been carried out using ultrasophisticated techniques in specialized university research laboratories and are not yet available for common diagnostic clinical use. We still have to rely on the sometimes confusing terminology and laboratory testing.

One of the earliest classifications was based on whether the major activity of the defective enzyme system is associated with the liver (hepatic) or with the bone marrow (erythropoietic). Often however the same defective metabolic process takes place in both organs. The porphyrias can also be classified by identifying the specific tissues in which the abnormal porphyrin concentrations exert their major toxic effects such as in the skin where they are called cutaneous porphyrias or in the liver where they are called hepatic porphyrias. Other organs such as the nervous system are frequently affected. The disease may be considered to be acute with the sudden onset of serious life threatening symptoms, or it can be chronic with only minimally bothersome intermittent problems that develop gradually over months and persist for years. Very frequently, the disease is classified as latent because the patient is asymptomatic until some other outside stimulus such as drugs or sunlight initiates the onset of symptoms in a person who has the genetic predisposition for this disease. In these cases the patient may not even be aware that they are suffering from porphyria until something happens to change the activity of the enzyme system and precipitate the symptoms of the disease.

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