Causes of Porphyria
The porphyrin molecules are synthesized in the body from simple molecules made up of carbon, nitrogen, hydrogen and oxygen. These molecules are joined together by specific enzymes to form 5-aminolevulinic acid (ALA), then porphobilinogen (PBG) and then on to the pyrrole rings. Each of the pyrrole rings has two side chains and when the four pyrrole ring structures condense together to form a tetrapyrrole, the combination of the eight side chains can form several variations called isomers. These isomers undergo further reactions where the side chains lose small segments and form an extensive variety of different molecules, all called porphyrins, each with its own physico-chemical and biochemical properties. Most of these porphyrin molecules, which are not involved in normal metabolic processes, are produced in small amounts and are destroyed or eliminated as quickly as they are formed. These porphyrin degradation products are almost always water-soluble and are excreted in the urine as uroporphyrins and in the stool as coproporphyrins. Only a very few of these isomers are clinically important and essential for life. The one with the highest concentration is the porphyrin molecule incorporated in haemoglobin, 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. Haemoglobin is found in red blood cells and as the red blood cells age, the cells are degraded and the porphyrin ring structures of the haemoglobin are ruptured to form a long chain molecule called bilirubin. It is bilirubin that 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, remodelling and destruction of the porphyrins occurs in a sequence of chemical reactions under the control of enzymes. Enzymes are large protein molecules 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 involved in that reaction. As a result, they influence the concentrations of both the precursor and end products of the specific reaction. These enzymes are specified by the deoxyribonucleic acid (DNA) that is present in the chromosomes contained within the nucleus of the cells. The segment of DNA that specifies a particular protein is called a gene. The gene is a template for the synthesis of messenger ribonucleic acid (mRNA). mRNA specifies how amino acids are liked together to form a protein.
If the DNA composition of the gene is defective or abnormal (i.e. contains a mutation), the metabolic functions that it controls may be defective as well.
Each human cell contains twenty-three pairs of chromosomes, one of each pair is from their mother and one from their father. Therefore, each gene is represented twice, one being on the father’s chromosome and one on the mother’s chromosome. If only one member of a pair contains a mutation, and the metabolic process specified by that gene is altered, then that mutation is said to be dominant. If both members of a pair must each contain a mutation before the metabolic process is altered, then that mutation is said to be recessive.
Although usually the gene is passed on unaltered from parent to child, occasionally a change in the structure of the gene, called a mutation can occur. Many of the mutations of the individual genes involved in porphyria have been identified. 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. 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. 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 otherwise latent cases.
Source: This information originally appeared in a booklet written for the Canadian Porphyria Foundation: A Guide to Porphyria (1991) by Dr. Barry A. Tobe, MD, Ph.D, FRCP(C), Toronto, Ontario, Canada. The content has been updated by Dr. Brian M. Gilfix, MDCM, PhD, FRCPC, DABCC, FACB on 22/03/2015.
Last Updated: 22/March/2015