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A Guide To Porphyria

DESCRIPTIONS OF THE TYPES OF PORPHYRIA

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. There are several mutations of a 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 liver cells. 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 blocks 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 menstrual cycles. 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 an abnormal accumulation 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 the development of peripheral neuropathies with muscle pain and weakness and changes in sensation. The muscle weakness can progress to respiratory insufficiency. In addition hallucinations, confusional states and acute psychiatric syndromes can be identified and occasionally seizures will occur. The autonomic nervous system may be involved with the patient developing 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 PBG and ALA in both random samples and 24 hour collections. The activity of the enzyme PGB.D can be measured in one of the special university referrence centers, but the time taken to get the test results back should not delay therapy if the diagnosis seems likely. Sometimes, during an acute attack, the 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 with narcotic analgesics, often in very large doses, may be essential. Anxiety can often be settled by the use of chlorpromazine by mouth or by injection and some autonomic 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. The abnormal over production of ALA can be stopped by the administration of hematin or heme arginate, and this is usually effective in stopping the attacks. If the attacks are associated with menstruation, therapy may be warranted with the use of blocking hormones such as birth control pills or LHRH analogues such as leuprolide. 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 porphyria 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, which is thought to be located on chromosome number 9 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 PBG and ALA in the urine. The treatment is essentially the same as for AIP, with hematin usually being effective.

Variegate Porphyria (VP)
Variegate porphyria is a type of porphyria that is associated with the symptoms of the neurovisceral crises similar to the patient with AIP but is also associated with a classic photosensitive skin disorder. The defective gene is located on chromosome number 1and 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 Afrikan population of South Africa. 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 findings of the standard nonspecific form of skin sensitivity to solar radiation. These changes include skin fragility, erosions and blisters during the acute attack, and abnormal pigmentation, skin thickening and hirsuitism due to 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 very little clinical 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 PBG and ALA 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 porphyrins. 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 technically very difficult to measure.

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 cells. When its concentration is decreased or its activity inhibited there is an over accumulation of uroporphyrin and other highly carboxylated porphyrins which are concentrated in the skin. Due to their propensity to accumulate radiant energy through a photodynamic process, they can inflame the tissues and cause cutaneous symptoms.

In about 20% of cases, the disease is inherited as an autosomal dominant trait and asssociated 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. About 80% of cases of PCT do not have a familial history 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 pathologic state. Excessive alcohol ingestion has long been recognized as an important cause, possibly related to the development of chronic liver disease. Estrogen therapy may also be a factor in this disease. Viral infections, particularly the HIV and hepatitis C viruses have been implicated. 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 with abnormal red cell and iron metabolism are also important causes.

The predominant symptom is that of photosensitivity, with abnormalities on the areas 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 increased skin fragility, hair growth, scarring and pigment deposition. These findings are 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. There is an overproduction of water soluble porphyrins, particularly uroporphyrins, and they spill out into the urine and bile with the result that the urinary and fecal concentrations of these compounds are elevated. Urinary PBG and ALA excretions are unaffected and are normal. Plasma porphyrin concentrations are increased, particularly the uroporphyrin levels. During clinical remissions, these abnormal levels fall to normal.

It is often difficult to differentiate PCT from VP or HCP, even in the laboratory as some patients with VP will not have elevated urinary PBG levels and plasma and stool examinations are usually warranted. It is important to try to differentiate between PCT and VP since patients with PCT do not have to be concerned 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 may also be of benefit.

Lead poisoning should also be included in this category 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 protoporphyrin 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 in 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 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 activitated charcoal may help eliminate the protoporphyrins from the body.

Rare forms of porphyria

Amino levulinic acid dehydratase deficiency (ALAD) is a very rare form of porphyria that is inherited in an autosomal recessive fashion and has been diagnosed in a very small number of patients whose ages range from 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 affected by chronic 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. It occurs at a very young age. The urinary porphyrins are markedly increased and often stain 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.

Hepatoerythropoietic porphyria (HEP) is associated with a marked deficiency in the activity of uroporphyrinogen decarboxylase. It differs from familial PCT where there is only about a 50% reduction and it can be considered to be a 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.

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