Porphyrins are a group of chemical compounds that occur in most living cells in both animals and plants. These organic compounds are combined with metals such as magnesium in the plant kingdom to produce chlorophyll and with iron in the animal kingdom to produce heme. They are involved in the control of the electron transport systems of the organism and are localized in the intracellular organelles called mitochondria. The mitochondria influence the production, accumulation and utilization of energy. The term porphyria refers to a group of diseases in animals, particularly humans that are caused by the overproduction and accumulation of groups of porphyrins and porphyrin precursors in specific and typical patterns. Each type of porphyria is associated with a specific accumulation of porphyrin compounds and precursors to induce a relatively consistent constellation of symptoms, clinical findings and biochemical abnormalities. The metabolic defects that are associated with this condition are localized primarily in the liver, the bone marrow and the red blood cells and are associated with demonstrable abnormalities in individual enzyme activities.
The porphyrin synthetic pathway begins with the combining of glycine and succinyl coenzyme A to form delta-aminolevulinic acid (ALA). Two of these molecules condense to form a single pyrrole ring structure called porphobilinogen (PBG). Four of these small pyrrole rings are joined to ultimately form a large ring configuration or tetrapyrrole compound called protoporphyrinogen which, in turn, is the precursor of heme. This large ring structure has a specific spacial configuration that enables it to hold an activated iron molecule in the center of the ring in such a way that it can react with reactive molecules such as oxygen. This type of iron porphyrin complex, when attached to the protein called globin is called hemoglobin. It is this combination of the three segments, porphyrin, iron and globin that enables oxygen to be bound and transported preferentially by the red blood corpuscles since they contain large amounts of hemoglobin. The oxygen is picked up and bound to the hemoglobin in the lungs and then released in peripheral tissues by physico-chemical reactions. This particular ring configuration of the porphyrins usually gives them a red colour. Some porphyrins are colorless but will turn red when exposed to sunlight. A similar porphyrin structure in plants when combined with magnesium and a different protein forms chlorophyll which gives the plants their characteristic green colour.
The porphyrin molecules are synthesized in the body from simple amino acids which contain carbon, nitrogen, hydrogen and oxygen. These amino acids interact under specific enzymatic protoporphyrinogen. Since the side chains of the pyrroles vary in their composition there can be several different forms or isomers of this large ring structure. These isomers undergo further reactions where they lose little segments containing carbon, hydrogen and oxygen and form a variety of different molecules, all called porphyrins, but each has its own physico-chemical and biochemical properties. Most of these porphyrin molecules are not needed for 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 soluble and are excreted in the urine as uroporphyrins and in the stool as coproporphyrins. Only two of the isomers are clinically important and essential for life. The one with the highest concentration is hemoglobin which is concentrated in red cells, but the porphyrins are also present in the cytoplasm and are essential for many other metabolic processes. As the red cells age they in turn are broken down and the porphyrin ring structures are ruptured to form a long chain molecule called bilirubin. This is coloured yellow green and is excreted by the liver into the bile. Most of the metabolic processes involving the porphyrins occurs in the liver and in the bone marrow.
Each step in the making, restructuring, destruction and degradation of the porphyrins is carried out by a sequence of chemical reactions under the control of a series of enzymes. These enzymes are large protein molecules and are present in either the cytoplasm or the mitochondria of cells. Both the concentration and the activity of the enzymes control the rate of each specific chemical reaction and, as a result they influence the concentrations of both the precursor and end products of the reaction. These enzymes are under the control of the DNA which is present in the chromosomes contained within the nucleus of the cells. The chromosomes present in each cell have multiple condensations of coiled DNA which are called genes. The DNA in these intranuclear genes makes RNA molecules, called messenger RNA which regulate the production of proteins including these enzyme systems contained within the cell.
In general, each gene has several functions, and for the most part each enzyme system is under the control of multiple genes although the specific porphyria enzymes seem to be encoded by single gene loci.. If the DNA structure 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 which case there will be no metabolic derangement. Rarely, both genes may have the recessive characteristics, in which case the metabolic functions will be significantly altered. Although most of the time the gene is passed on intact, from parent to offspring via the ovum or sperm, occasionally a change in the structure of the gene can occur, sometimes spontaneously and sometimes due to radiation, medications, etc. These changes are called gene mutations. There may be multiple mutations associated with individual genes. Many of the mutations of the individual genes involved in porphyria have been identified. Thus the children of porphyric patients may be at risk of inheriting their parent's disease, but not always. 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 retarded there may be a build up of potentially toxic precursors; if the chemical reaction is too fast the end products may accumulate in too high a concentration; and often the abnormal enzyme systems redirect 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 so affect the body in a different way. Most compounds are simple 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 which will then be aborted; other times the metabolic abnormality will not become apparent until after puberty or even middle age. Frequently nothing will happen unless the enzyme abnormalities are brought out 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.
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 is somewhat unsatisfactory and illogical. It theoretically would be preferable to classify the porphyrias on the basis of the specific gene or enzyme defects giving rise to the abnormal porphyrin 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 available for common diagnostic 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 bother organs. The porphyrias can also be classified on 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 precipitate the symptoms and bring out the disease.
Acute Intermittent Porphyria (AIP)
This form of porphyria is perhaps the most severe of all of the porphyric syndromes in terms of its symptomatology. It is inherited in an autosomal dominant fashion and is slightly more common in females than in males. Researchers have described several mutations of the single gene, located on chromosome 11, which controls the activity of the enzyme porphobilinogen deaminase (PGB.D). This enzyme is responsible for the joining of 4 porphobilinogen molecules into a linear chain to form a compound called hydroxymethylbilane which is then converted into the cyclic or ring structure characteristic of the porphyrin molecule. The intracellular activity of the enzyme PGB.D in patients with AIP is decreased, usually to less than 50% in both red blood cells and cells obtained from the liver. Usually the enzyme activity at this level is adequate for normal body functions, so that this deficiency is not clinically apparent unless some other stimulus interferes with the enzyme system, at which time an acute attack can occur.
These triggers include an extensive array of exogenous factors such as starvation or unusual diets, street drugs, alcohol, prescribed medications and environmental stimuli. Endogenous stimuli are also often involved including stress, intercurrent illness and normal cyclic menstrual periods. When an attack occurs, the activity of the enzyme becomes further impaired, there is a rapid accumulation of the precursor compounds PBG and ALA and the patient becomes acutely ill. The biochemical or physiologic mechanisms for the development of the neurologic symptoms have yet to be clearly defined, but it appears to be related to a build up of ALA at the nerve endings which acts either as a direct neurotoxin or interferes with neurotransmission.
The symptoms include abdominal pain and cramps, nausea and vomiting, diarrhea or constipation, urinary retention, and peripheral neuropathies with muscle weakness or changes in sensation. In addition hallucinations, confusional states and acute psychiatric syndromes can be identified and occasionally seizures will occur. The autonomic nervous system is involved with a rapid heart rate and high blood pressure. The neuroendocrine parts of the brain can also be affected and bring about decreases in the blood levels of sodium and magnesium which in turn can cause other clinical problems. The diagnosis of AIP is based primarily on clinical signs and symptoms and is supported by the laboratory finding of positive urine screening tests with increased levels of ALA and PBG both in random samples and 24 hour collections. The activity of the enzyme PGB.D may be able to measured in one of the special university referral centers, but the time taken to get the test results back should not delay therapy if urine colour turns brownish red after exposure to bright sunlight due to the condensation of high concentrations of PBG to red coloured porphyrin complexes. This discoloration of the urine is often an important clue to help in the diagnosis of this disease. Occasionally the patients themselves note that their urine turns reddish brown a day or so before the onset of their symptoms and clears as they get better.
Frequently the acute attacks disappear with little medical intervention but occasionally the patient has to be hospitalized. The offending or precipitating causes should be identified and eliminated. High concentrations of glucose and other carbohydrates given either orally or intravenously are helpful and should be initiated at the first signs of this disease. The relief of pain with analgesics such as morphine or Demerol may be essential often in very large doses. Anxiety can often be settled by the use of manifestations such as rapid heart rates and high blood pressure will respond to the beta-blocker group of drugs, such as propanalol. Seizures can be treated with either magnesium or gabapentin, a new anticonvulsant which is thought to be the safest of the anticonvulsants currently available. The abnormal over production of ALA can be stopped by the administration of hematin or heme arginare, and this is usually effective in stopping the attacks. If the attacks are associated with the menstrual cycles, therapy may be warranted with the use of blocking hormones such as birth control pills or LHRH analogues such as leuprolide. This therapy requires a team approach involving gynecologists along with other doctors. The prognosis of the acute attacks is good and most symptoms settle quickly although at times the severe nerve damage and its associated signs of weakness and sensory disturbance may take several months to improve.
Hereditary Coproporphyria (HCP)
This uncommon type of poprhyria is associated with a reduction in the activity of the enzyme coproporphyrinogen oxidase to less than 50% of its usual activity. It is inherited in an autosomal dominant fashion, is more frequent in females than males and is classified as a type of hepatic porphyria since there is an excess accumulation of coproporphyrin in the liver. Most people with the defective gene have no symptoms. The heterozygous carrier may develop symptoms after puberty while the homozygous disease can start in infancy and be quite serious. The clinical symptoms are similar to those of AIP but it can be associated with the type of photosensitive dermatitis seen in PCT. Fatigue and muscle weakness are symptoms and sometimes the patient may be jaundiced. There are marked increases in the excretion of coproporphyrins in the urine and feces and there are usually increased excretions of ALA and PBG in the urine. The treatment is essentially the same as for AIP, with hematin usually being very effective.
Variegate Porphyria (VP)
Variegate porphyria is a type of porphyria that is associated with the symptoms of the neurovisceral crises simeilar to the patient with AIP but is also associated with a classic photosensitive skin disorder. It is inherited in an autosomal dominant fashion. The rate limiting enzyme is protoporphyrinogen oxidase (PPO) which controls one of the final stages of heme synthesis, the oxidation of protoporphyrinogen-IX to protoporphyrin. In patients with this disease, the activity of PPO is reduced by at least 50%. It is relatively common in the white African population of South Africa and is rarely seen in people of native African descent. The disease rarely appears before puberty, is most common in the young adult but may suddenly occur at any age including the elderly.
The neurovisceral crises give symptoms similar to those of patients suffering from AIP, while the photodermatitis shows the typical finding of the standard nonspecific form of skin sensitivity to solar radiation. These skin changes include skin fragility, erosions and blisters in the acute attack, and abnormal pigmentation, skin thickening and kirsuitism with chronic exposure. The precipitating factors are also similar to those of AIP although some experts feel that the acute attacks of VP are not related to menstrual cycles. There is little evidence to show that VP is a cause of long term psychiatric disease. With an acute attack, the urine may turn red and there is always an increase in the excretion of ALA and PBG in the urine. There are increased porphyrins in the urine with coproporphyrins excreted in excess of uroporphyrins. The severity of the attack may be related to the concentration of these prophyrins. Increased levels of both protoporphyrin and coproporphyrin are also found in the feces. These abnormal findings may return to normal when the disease is quiescent or in remission. Many people who are asymptomatic carriers of the abnormal gene will consistently have negative laboratory tests. The enzyme PPO is not present in red cells and is very difficult to measure even in research laboratories.
The treatment of the neurovisceral attacks is similar to that used in AIP, including the administration of hematin. The standard dermatological therapies for photodermatitis are usually ineffective and patients should be advised to avoid sun exposure and to use sunscreens containing zinc oxide or titanium oxide. If both parents carry the abnormal gene so that the patient is homozygous, the disease will present in early childhood and be rather severe. However the outlook for the heterozygous individual is good.
Porphyria Cutanea Tarda (PCT)
Porphyria cutanea tarda is the commonest of all the porphyrias. It is a skin disease only and is caused by decreased activity of the final enzyme step in the heme biosynthetic pathway, called uroporphyrinogen decarboxylase (URO.D). This enzyme is present primarily in the liver although it is also found in the red blood cells. When it concentration is decreased or its activity inhibited carboxylated porphyrins which are concentrated in the skin. Due to their propensity to store radiant energy, and through a photodynamic process, they irritate the tissues and cause cutaneous symptoms.
In about 20% of cases, the disease in inherited as an autosomal dominant trait and associated with deficient activity of URO.D in both the red cells and the liver. The onset of this inherited disease is usually delayed into adulthood although cases can occur in children. Most cases of PCT do not have a familial history (about 80%) and are called sporadic, toxic or acquired. There may however be a demonstrable genetic defect in many of these cases. This type of PCT is associated with deficient enzyme activity only in the liver which itself may be involved in a pathological state. There are several precipitating factors that have been identified. Excess alcohol ingestion has long been recognized as an important cause, possibly related to the development of chronic liver disease. Estrogen therapy may also cause this disease. Viral infections, particularly HIV and hepatitis C viruses have been implicated and hepatitis B may also be a factor. PCT can occur in patients receiving long term renal hemodialysis. Certain halogenated hydrocarbons have been associated with PCT. These compounds which have been contained in fungicides and herbicides were often inhaled or ingested by accident. Iron overload states may cause or magnify the disease. In addition, hematologic diseases associated wit abnormal red cell and iron metabolism are also important causes.
The predominant symptom is that of photosensitivity, with abnormalities on the ares of the skin exposed to light such as the face, the arms and the backs of the hands and wrists. There is irritation and blistering followed by increases in skin fragility, hair growth, scarring and pigment deposition. These finding are diagnostically not specific for PCT and are seen in other types of porphyria such as congenital erythropoietic porphyria as well as other types of skin disorders including a condition called pseudoporphyria. Since there is an overproduction of water soluble porphyrins, particularly uroporphyrins, they spill out into the urine and bile with the result that the urinary and fecal concentrations of these compounds are elevated. Urinary ALA and PBG excretions are unaffected and are always normal. Plasma porphyrin concentrations are increased, particularly the uroporphyrin levels. During clinical remissions, these abnormal levels fall to normal.
Some patients with VP may not have elevated PBG excretion levels, and may be confused with PCT unless plasma or stool analysis are carried out. It is important to try to differentiate between PCT and VP since patients with PCT do not have to worry about avoiding those drugs that may be dangerous in VP and the treatment of the two is also different. The treatment of this disorder is usually quite successful. The aggravating factors should be removed or controlled where ever possible. Repeated removal of blood (phlebotomies) at regular intervals to reduce the iron stores may be all that is required. The antimalarial drug, chloroquine in low dose has proven to be effective and the sun screen skin lotions with beta-carotene are also helpful. The treatment of the viral hepatitis C infection with interferon may be of benefit.
Lead poisoning might also be include in this group although it is somewhat different in that it interferes with the porphyrin biosynthetic pathways at several levels and may cause a rise in ALA levels without an increase in PBG levels. Red cell protoporphrin levels may also be increased in lead poisoning. There is however no photosensitivity in this condition.
Erythropoietic Protoporphyria (EPP)
This type of porphyria is caused by an enzyme defect in the last step of heme synthesis which is the insertion of the activated iron molecule into the middle of the protoporphyrin ring and is due to a partial deficiency of the enzyme called ferrochelatase. It is autosomal dominant in inheritance and the primary source of this excess production appears to be the bone marrow. there are marked accumulations of protoporphyrins in the juvenile red blood cells, and as the red cells mature the compound spills over into the plasma and is cleared by the liver and bile. Since protoporphyrin is poorly water soluble, it is not excreted in the urine but there is a marked increase in the concentration of protoporphyrin is the feces. The urine PBG and porphyrin concentrations are always normal. There is a male preponderance in distribution and the disease can come on in childhood.
The symptoms are precipitated primarily by sunlight and cause burning, itching, swelling and redness of the skin. Blistering and skin ulcers along with increase hair growth and pigmentation can follow chronic sun exposure. Occasionally liver disease may develop and gall bladder disease requiring surgery is a common problem because the high concentration of protoporphyrin in the bile will lead to gall stone formation. The photosensitivity of women with EPP seems to decrease during pregnancy with a corresponding decrease in red cell protoporphyrin levels. The treatment with the vitamin A analogue, beta-carotene and other sunscreens improves the tolerance to sunlight. The use of bile acid binding resins such as cholestyramine or activated charcoal may help in eliminating the protoporphyrins from the body.
Rare Forms of Porphyria
Amino Levulinic Acid Dehydratase Deficiency (ALAD):
is a very rare form of porphyria which is inherited in an autosomal recessive fashion and has been diagnosed in a very small number of patients whose ages range form infancy to adulthood. There is almost a complete lack of enzyme activity with increased excretion of ALA but not PBG in the urine. This enzyme is one of the main enzyme systems also affected by lead poisoning.
Congenital Erythropoietic Porphyria (CEP):
is also a very rare form of porphyria inherited as an autosomal recessive trait associated with a deficiency in the enzyme activity of uroporphyrinogen cosynthetase. The urinary porphyrins are markedly increased and often strain the diapers red. There is a marked degree of photosensitivity leading to considerable disfiguration due to scarring of the skin along with an enlarged spleen and a hemolytic anemia but no neurologic findings. Total avoidance of sunlight is usually essential to prevent further disfiguration. This is the only type of porphyria that can be diagnosed prenatally, and is characterized by the finding of elevated uroporphyrin concentrations in the amniotic fluid.
Hepaterythropoietic Porphyria (HEP):
is associated with a marked deficiency in the activity of uroporphyrinogen decarboxylase. It differs from familial PCT where there is only about 50% reduction and it can be considered to be homozygous variant of familial PCT. Marked phototoxic skin lesions develop early in childhood along with a variety of neurologic abnormalities.
There have been several case reports in the medical literature describing the coexistence of 2 types of porphyria in the same patient, these are also called dual porphyrias. These often present as difficult diagnostic problems as the clinical findings and laboratory results overlap. Fortunately they are very rare.
Copyright © 1999 "A Guide to Porphyria", Barry A. Tobe MD, Ph.D, FRCP. All rights reserved. [ http://www.cpf-inc.ca/index.htm]