Information from the Canadian Association for Porphyria, 2009
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 clinical 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 color. 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 sulfa drugs 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 ultra sophisticated 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.
How will it affect me?
People with porphyria should be able to lead full active enjoyable lives with a minimum of limitations or difficulties. Many people, probably the majority of those who have the propensity for porphyria, go through their entire lives with the inherited gene defects and never know they have this disease. They are called asymptomatic carriers and may be considered to have latent disease. A few people have repeated or intermittent attacks of symptoms separated by long intervals or remissions between illnesses. Unfortunately a very few patients can become very sick and on rare occasions patients have died. Both the quality of life and the longevity are normal in most patients with porphyria, particularly if the precipitating and inducing causes can be avoided.
What are the symptoms of porphyria?
The symptoms of each type of porphyria depend on the concentration of the specific porphyrin or porphyrin precursors that are overproduced. Accumulations of ALA and possibly PBG, as in acute intermittent porphyria affect nerve endings and can cause a variety of neurovisceral symptoms and specific neurologic syndromes. The symptoms involve the nerves to the gastrointestinal tract where severe abdominal pain, often severe enough to be confused with acute appendicitis can develop and lead to exploratory surgery. There can be emotional and psychiatric problems such as anxiety, insomnia, agitation, confusion, paranoia, depression and hallucinations, although there is little evidence to suggest that porphyria itself is a cause of any of the chronic psychiatric syndromes.
Seizures fortunately are rare, as the anticonvulsant medications commonly used to treat seizures have been known to precipitate acute attacks in some patients. Many forms of peripheral neuropathy may develop involving either the motor system causing weakness, or the sensory system causing funny feelings or loss of sensation in various areas of the body. The autonomic or involuntary nervous system can be affected leading to problems such as high blood pressure, excessive sweating, rapid heart rate and changing bowel and bladder functions including constipation and urinary retention. The serum levels of sodium and magnesium can also be diminished through involvement of the neuroendocrine system. The severity and extent of these symptoms will vary from patient to patient and from day to day, depending in part on internal or endogenous factors such as menstrual hormone cycles along with external or exogenous changes including exposure to stress, drugs, sunlight, alcohol and even fasting. Sometimes these symptoms can be identified soon after birth, but usually they do not become apparent until the patient is a teenager or young adult.
Another very important group of symptoms is related to the fact that the completed porphyrin ring structure has the ability to store radiant energy, usually ultraviolet light with a wave length of about 400nm. For the most part this radiant energy is derived from exposure to bright sunlight. This energy build up within the cells can damage the subcellular structures. Certain of the porphyrins because of their structure are better able to concentrate this radiant energy more than others. This process is called photosensitivity or phototoxicity and it can cause many skin abnormalities. In an acute illness exposure to sunlight can cause tingling, stinging or burning skin discomfort during or soon after, followed by redness, rashes and blistering. Skin changes associated with chronic diseases can include scarring, increased or decreased amounts of hair growth, thickening of the skin of the exposed areas and increased skin fragility. It differs from sun burn in that it is recurrent and usually is not associated with prolonged or intense exposure to sun light.
How is porphyria diagnosed?
The diagnosis of porphyria is often difficult to make, in part due to the fact that the symptoms can mimic many other clinical states and the fact that the disease is sufficiently rare that most doctors have very limited personal experience with it. The recollection that some other member of the family, even a distant cousin, had this problem is often the key to the diagnosis. Since the multiple disease syndromes known as porphyria are all due to defective enzyme functions, there are abnormal accumulations of a variety of compounds involved in the metabolic pathway. Some of these are water soluble and so are freely excreted in the urine, others are found in feces after being metabolized by the liver and excreted into the bile. The classic laboratory finding that is described is the demonstration of red urine, either immediately on being passed or after standing in bright sun light. This is due either to the excretion of preformed porphyrin molecules or possibly by the nonenzymatic condensation of the high concentration of PBG into tetrapyrrole porphyrin molecules.
Ideally, the laboratory diagnosis of porphyria should be based on either the identification of the DNA structure of the defective gene or the measurement of the activity of the specific enzyme system that is affected. These procedures are not as yet available on a routine basis. As a result, the laboratory diagnosis still depends primarily on the tests which will identify abnormal concentrations of either the precursors of porphyrins or the porphyrins themselves or both. The compounds which are usually measured include PBG, ALA, uroporphyrin and coproporphyrin, and they are found in the urine, feces, plasma and red blood cells. When the diagnosis of porphyria is considered clinically, the initial screening test should be the determination of the concentration of PBG and ALA in a random sample of urine. Porphobilinogen production is elevated in AIP, VP, and HCP. There are several procedures used for these tests and most laboratories have upgraded their protocols to use the newest techniques in order to make the screening tests more specific and sensitive. The diagnostic tests for urinary PBG, ALA and porphyrin excretion are done on a 24 hour collections of urine and require specific preservatives. The urine should be collected in an opaque bottle and refrigerated to prevent the breakdown of the compounds. These tests are often difficult for the patient to complete as the urine must be collected and stored under very specific conditions and not all laboratories can do these tests. Although a sick patient will usually cooperate with the instructions for collection and storage of a 24 hour urine sample, many asymptomatic possible carriers of the gene who are being screened will not bother. In addition, the results are often not a true reflection of the changing metabolic state of the patient, they may be technically unreliable and are often difficult to interpret when they are borderline positive.
It is essential that before arranging for these tests, the doctor consult with the laboratory to ensure that the tests are available and also know the recommended procedures as to how and when to collect the blood, stool and urine samples. In addition, there is considerable overlap of the laboratory results between the various diseases, which complicates the difficulties of making a specific diagnosis. It can be very difficult to identify the patients with latent disease, particularly youngsters before the age of puberty. Some specialized university based referral laboratories will make other tests available using more sophisticated techniques. The activity of the enzyme porphobilinogen deaminase which is deficient in patients with AIP can be measured in their red blood cells and is available in some reference laboratories. In addition the technique of high performance liquid chromatography can be used to accurately measure the concentrations of porphyrins in the urine, stool and plasma samples.
Is porphyria treatable?
Simply put, the answer is yes. Prevention of the acute attacks in both known sufferers of the disease and suspected latent carriers is the most important approach. In a known porphyric patient it is essential to identify the factors that can precipitate the acute symptoms. The avoidance of porphyrogenic medications, bright sunlight or alcohol is often all that is necessary to avoid these attacks. In women with repeated premenstrual relapses, the inhibition of ovulation by the use of pituitary hormones or the LHRH analogues such as leuprolide may be effective in reducing their frequency. High carbohydrate diets are also helpful.
During the acute attacks, supportive therapy is required including narcotic analgesics, tranquilizers such as chlorpromazine, antinauseants, rehydration, sodium and magnesium replacement, high carbohydrate diets and sometimes intravenous therapy with high concentrations of glucose. Hematin and heme arginate, which are essentially the final products of the heme biosynthetic pathway can be given intravenously and act as specific agents to treat several types of porphyria by decreasing the activity of the enzyme ALA synthase, the first step in the heme biosynthetic cascade. The reduced activity of this enzyme slows down the entire metabolic pathway and stops the overproduction of ALA and PBG. However this drug must be used with caution as it can be associated with side effects.
During severe attacks the patient may on occasion require hospitalization. Seizures are often a difficult problem to control since many of the drugs used to control epilepsy such as Dilantin may precipitate or worsen attacks of porphyria. The anticonvulsant gabapentin has been shown to be effective and safe. Each type of porphyria has its own specific therapeutic program and it is important to try to identify the specific enzyme defect if possible. In cases of iron overload or lead toxicity the removal of the offending heavy metal excess may be all that is required. There appears to be some evidence that the treatment of hepatitis C with interferon and ribaviron may also be effective.
There are several drugs and medications used to treat other diseases that can precipitate an acute attack, but there are many more that are safe. It is preferable to take only the medicines that are absolutely essential. Before the patient with porphyria takes any drug they must ensure its safety. This is often difficult because of the limited experience of doctors, pharmacists and even university clinics in this field. If possible the family should check with the drug manufacturer or distributor about its porphyrogenic properties and history. The drug companies usually keep records of drug side effects. Most pharmaceutical houses have toll free phone numbers and are able to provide this information readily by fax or telephone. It is also important that the patients and the doctors share their knowledge and experience as widely as possible.
What about surgery or pregnancy?
Although there may be a risk of precipitating an acute attack of porphyria when a patient requires surgery, this problem can be either avoided or controlled by the application of preventative measures and the use of appropriate drugs and anaesthetic agents by knowledgeable physicians. However the entire medical team must be conversant with this disease. The risk of problems arising during pregnancy is also relatively minor and the symptoms can be easily managed. Every patient with porphyria should wear or carry with them some type of identification such as a Medic-Alert bracelet indicating the fact that they may be at risk for porphyria. Rather than concealing the fact, they should also ensure that their close family and friends know about their condition. The individual patient should make a point of becoming as knowledgeable as possible about their disease and their health.
What about my children?
Since porphyria is caused by a defective gene, it means that the children can be affected if one of the parents has porphyria. The inheritance of this gene can be classified as either dominant, in which case there is a 1 in 2 chance that the child will develop the disease, or as recessive in which case it will be very unlikely for the offspring to develop the problem. Although most types of porphyria are associated with a dominant inheritance pattern, the majority of the carriers of these abnormal genes will have latent disease and never develop symptoms and not be aware of this problem throughout their entire lives. Genetic counseling is available but most patients prefer to go about their lives in a normal fashion and deal with their family planning in their own personal fashion. The screening tests for porphyria may not become positive until after puberty but some clinics recommend periodic testing every few years starting at age 10 for children at risk of this disease. Many young patients do not bother with this testing since the test results are often unreliable and prefer to adopt a 'wait and see' attitude, while still following the appropriate preventative protocols.
Considerable progress has been made in the understanding of the genetic defects giving rise to the clinical and biochemical features of porphyria. The genes have been identified and decoded and mouse models of the disease have been made by genetic engineering. This should enable scientists to assess new treatments and allow pharmaceutical companies to test new drugs for their porphyrogenic properties. However these research advances have yet to be transferred into significant changes in the standard bedside medical practices and laboratory diagnostic techniques. It can be anticipated that this will change reasonably soon. Some very sick patients may benefit by the newer techniques of bone marrow and liver transplantation. However specific gene therapy is still a long ways away.
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