Porphyria
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What is Porphyria?
Porphyria is not a single disease but a group of at least eight disorders that differ considerably from each other. A common feature in all porphyrias is the accumulation in the body of "porphyrins" or "porphyrin precursors". Although these are normal body chemicals, they normally do not accumulate. Precisely which of these chemicals builds up depends upon the type of porphyria.
The clinical manifestations of the different types of porphyria are not the same. Forms of treatment also depend on the type of porphyria. Therefore, it is difficult to make general statements that apply to all these disorders.
The symptoms arise mostly from effects on the nervous system or the skin. Effects on the nervous system occur in the acute porphyrias. Proper diagnosis is often delayed because the symptoms are nonspecific. Skin manifestations can include burning, blistering and scarring of sun-exposed areas.
The terms "porphyrin" and "porphyria" are derived from the Greek word "porphyrus" meaning purple. Urine from some porphyria patients may be reddish in color due to the presence of excess porphyrins and related substances, and the urine may darken after standing in the light
How does one get Porphyria?
In each type of porphyria there is a deficiency of a specific "enzyme". These enzymes are involved in the synthesis of heme, a substance important to many body functions and found in largest amounts in the bone marrow, red blood cells and the liver. Heme exists as hemoglobin in the bone marrow and red blood cells but has other functions in other tissues such as the liver. The type of porphyria present is determined by which enzyme is deficient. These enzyme deficiencies are usually inherited. Environmental factors, such as drugs, chemicals, diet and sun exposure can, depending on the type of porphyria, greatly influenced the severity of symptoms.
The inherited porphyrias are either autosomal dominant (inherited from one parent) or autosomal recessive (inherited from both parents). "Autosomal" genes always occur in pairs, with one coming from each parent. Individuals with an autosomal dominant form of porphyria have one abnormal gene paired with a normal one, and half of their offspring (on the average) will inherit the gene for the disease, while the other half will inherit the normal gene. Some of those who inherit the abnormal gene will develop symptoms. Individuals with an autosomal recessive type of porphyria have a pair of abnormal genes, and each of their children will inherit one abnormal gene for that disease, which will be paired with a normal gene from the other parent, and there will be no symptoms. If two carriers of the same abnormal recessive gene marry, approximately one fourth of their children will inherit two abnormal genes, and these children will develop symptoms of the disease. Because all porphyrias are uncommon, it is very unlikely that more than one type will occur in the same family, or that someone with one type of porphyria will go on to develop another.
How are the Porphyrias Classified?
The best way to classify a case of porphyria is to determine which enzyme is deficient. The enzymes that are deficient in the porphyrias normally act in sequence to make heme from simpler molecules. Heme is a vital substance for all body organs and consists of an iron atom surrounded by a porphyrin molecule.
Sometimes, other classifications are useful. For example, the porphyrias are often divided into two groups, the "hepatic" and "erythropoietic" types. Porphyrias with skin manifestations are sometimes called "cutaneous porphyrias". The "acute porphyrias" are those characterized by attacks of pain and other neurological manifestations. These "acute" symptoms can be both rapidly-appearing and severe. An individual may be considered "latent" if he or she has the required enzyme deficiency but has never developed symptoms. There can be a wide spectrum of severity between the "latent" and "active" cases of any particular type of porphyria.
What Treatment and Prevention are Available?
Treatment depends greatly on the type of porphyria and can be quite successful. Preventive measures, which include avoidance of certain drugs and alcohol, are also important in those who are identified as having inherited porphyria, even if they have never had symptoms. Asymptomatic carriers as well as patients who have symptoms should be educated about preventive measures.
Is Porphyria Progressive or Lethal?
Unlike some genetic diseases in which all individuals who inherit an abnormal gene become ill, the severity of porphyria varies considerably. Such variability is due to certain "additional factors" other than the gene itself. Consequently, risks of severe medical difficulties or even death in the "acute" porphyrias are often diminished when affected individuals are well informed of their diagnosis and adopt suggested precautionary measures. Even with modern treatment and prevention, some patients still have repeated attacks. However, progressive deterioration and death from paralysis in the "acute" porphyrias are very unusual.
Is Sunlight Always Harmful?
Sun sensitivity can occur in all but two types of porphyria. The degree of sensitivity to sunlight varies considerably. Patients with sun sensitivity have high levels of porphyrins in the blood plasma which, depending on the type of porphyria, have originated from the liver or the bone marrow. Ultraviolet light interacts with porphyrin in such a way as to damage skin tissue. Some treatments may help patients tolerate sun exposure even without lowering porphyrin levels. In some cases, treatment can lower porphyrin levels, and sunlight can be tolerated
Summary of each type of Porphyria
ALAD Porphyria (ADP)
This form of porphyria is inherited as an autosomal recessive trait and seems to be extremely rare. The symptoms are very similar to acute intermittent porphyria. There is a deficiency of the enzyme delta-aminolevulinic acid dehydratase (ALAD) and increased excretion of delta-aminolevulinic acid (ALA) in the urine.
Acute Intermittent Porphyria (AIP)
This is one of the hereditary hepatic porphyrias. Its inheritance is autosomal dominant. The deficient enzyme is porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase. This enzyme was formerly known as uroporphyrinogen I-synthase, and this term is still used by some clinical laboratories. A deficiency of PBGD is not sufficient by itself to produce AIP, and other activating factors must also be present. These include hormones, drugs and dietary changes. Sometimes, activating factors cannot be identified.
Symptoms: Most individuals who inherit the gene for this type of porphyria never develop symptoms. AIP becomes manifest after puberty, especially in women due to hormonal influences. Symptoms usually occur as attacks that develop over several hours or days. Abdominal pain, which can be severe, is the most common symptom. Others may include nausea, vomiting, constipation, pain in the back, arms and legs, muscle weakness (due to effects on nerves supplying the muscles), urinary retention, palpitation (due to a rapid heart rate and often accompanied by increased blood pressure), confusion, hallucinations and seizures. Sometimes the level of salt (sodium and chloride) in the blood decreases markedly and contributes to some of these symptoms. The skin is not affected.
Diagnosis: Because this disease is rare and can mimic a host of other more common conditions, its presence is often not suspected. On the other hand, the diagnosis of AIP and other types of porphyria is sometimes made incorrectly in patients who do not have porphyria at all, particularly if laboratory tests are improperly done or misinterpreted. The finding of increased levels of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine establishes that one of the acute porphyrias is present. If PBGD is deficient in normal red blood cells then the diagnosis of AIP is established. However, measuring PBGD in red blood cells should not be relied upon by itself to exclude AIP in a sick patient, because the enzyme is not deficient in red blood cells of all AIP patients.
If it is known that someone in a family has AIP and their enzyme value is low in red blood cells, other family members who have inherited a deficiency of PBGD can be identified by measuring the enzyme in their red blood cells. Latent cases so identified can avoid agents known to cause attacks. However, in some AIP families, PBGD is normal in red blood cells and is deficient only in the liver and other tissues. Falsely low values sometimes occur due to problems with collecting and transporting the sample.
DNA is the material in cells that encodes all the genetic information of an individual. Many different mutations have been identified in the portion of DNA that comprises the gene for PBGD. Almost every family with AIP has a different mutation in this gene. Within one family, however, everyone who inherits a deficiency of PBGD has the same mutation. It is advantageous to know the precise mutation in a family, because that knowledge enables the identification of AIP gene carriers by DNA testing. This approach is much more precise than measuring PBGD enzyme activity in red blood cells. At present, DNA testing for AIP and other porphyrias is available only through a few research laboratories.
Treatment and Prognosis: Hospitalization is often necessary for acute attacks. Medications for pain, nausea and vomiting, and close observation are generally required.
A high intake of glucose or other carbohydrates can help suppress disease activity and can be given by vein or by mouth. Intravenous heme therapy is more potent in suppressing disease activity. It can be started after a trial of glucose therapy. However, the response to heme therapy is best if started early in an attack. Therefore, delaying heme therapy until glucose alone has not been effective may not be warranted unless an attack is mild.
Heme must be administered by vein. Panhematin®, from Ovation Pharmaceuticals, Inc., is the only commercially available heme therapy for treatment and prevention of acute porphyric attacks in the United States. Heme arginate, which is marketed in some other countries, is another preparation of heme for intravenous administration. It is however, not presently available in the United States. Panhematin® is less likely to produce phlebitis if it is mixed with human albumin before it is given. (Directions for preparing Panhematin® in this manner can be obtained from porphyria specialists.) Heme therapy is seldom indicated unless the diagnosis of acute porphyria is proven by a marked increase in urine PBG. How heme therapy should be used to prevent attacks is not well established.
During treatment of an attack, attention should be given to salt and water balance. Harmful drugs should be stopped. These include barbiturates, sulfonamides, and many others. Attacks are often precipitated by low intake of carbohydrates and calories in an attempt to lose weight. Thus dietary counseling is very important (see below). Premenstrual attacks often resolve quickly with the onset of menses; hormone manipulations may prevent such attacks.
AIP is particularly dangerous if the diagnosis has not been made and if harmful drugs are administered. The prognosis is usually good if the disease is recognized and if treatment and preventive measures are begun before severe nerve damage has occurred. Although symptoms usually resolve after an attack, some patients develop chronic pain. Nerve damage and associated muscle weakness can improve over a period of months or longer after a severe attack. Mental symptoms may occur during attacks, but are usually not chronic.
Wearing a Medic Alert bracelet is advisable for patients who have had attacks but is probably not warranted in most latent cases. It should be remembered that AIP patients can develop other diseases, and symptoms may not always be due to porphyria.
Diet: AIP patients prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intakes of carbohydrate and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician who may then request that a dietitian estimate an individual's normal caloric intake, which varies greatly from one person to another. Then it may be appropriate to prescribe a diet that is approximately 10% below the normal level of calories for the patient. This should result in a gradual weight loss and usually will not cause an attack of porphyria.
Having Children: Pregnancy is tolerated much better than was formerly believed. Offspring have a 50% chance of inheriting the gene for AIP, but the great majority of them remain "latent" for all or most of their lifetimes. The minority that eventually have symptoms usually benefit from treatment. Given these considerations, most patients or individuals with "latent" porphyria elect to have children for the same reasons as anyone else.
Congenital Erythropoietic Porphyria (CEP)
This disease is extremely rare and is autosomal recessive. It is also known as Gunther's disease. The deficient enzyme is uroporphyrinogen III cosynthase (or uroporphyrinogen III synthase). Various mutations in the gene for this enzyme have been identified in different families. As is characteristic of the erythropoietic porphyrias, symptoms begin during infancy. Sometimes CEP is recognized as a cause of anemia in a fetus before birth. In less severe cases symptoms may begin during adult life. Porphyrins are markedly increased in bone marrow, red blood cells, plasma, urine and feces. Porphyrins are also deposited in the teeth and bones.
Symptoms: Skin photosensitivity may be extreme and lead to blistering, severe scarring and increased hair growth. Bacteria may infect the damaged skin. Facial features and fingers may be lost through phototoxic damage as well as infection. Red blood cells have a shortened life-span, and anemia often results. Synthesis of heme and hemoglobin is actually increased to compensate for the shortened red blood cell survival.
Treatment and Prognosis: Blood transfusions and perhaps removing the spleen may reduce porphyrin production by the bone marrow. Activated charcoal given by mouth is sometimes effective. Bone Marrow Transplantation has been very effective in some patients. Stem Cell Transplantation and Gene Therapy may be used in the future.
Porphyria Cutanea Tarda (PCT)
This disease is the most common of the porphyrias and results from a deficiency of the enzyme, uroporphyrinogen decarboxylase (UROD), PCT is essentially an acquired disease, but some individuals have a genetic (autosomal dominant) deficiency of UROD that contributes to its development. These individuals are referred to as having "familial PCT". Most individuals with the inherited enzyme deficiency remain latent and never have symptoms.
PCT is one of the hepatic porphyrias. Large amounts of porphyrins build up in the liver when the disease is becoming active. The disease becomes active when acquired factors, such as iron, alcohol, hepatitis C virus (HCV), HIV,estrogens (used, for example, in oral contraceptives and prostate cancer treatment) and possibly smoking, combine to cause a deficiency of UROD in the liver. Hemochromatosis, an iron overload disorder, can also predispose individuals to PCT.
Symptoms: The symptoms in PCT are mostly confined to the skin. Blisters develop on sun-exposed areas of the skin, such as the hands and face. The skin in these areas may blister or peel after minor trauma. Increased hair growth, as well as darkening and thickening of the skin may also occur. Neurological and abdominal symptoms are not characteristic of PCT.
Liver function abnormalities are common but are usually mild. These sometimes progress to cirrhosis and even liver cancer. PCT is often associated with hepatitis C infection, which can also cause these liver complications. However, liver tests are generally abnormal even in PCT patients without hepatitis C infection.
Diagnosis: The preferred screening test for PCT is a measurement of porphyrins in plasma. This can differentiate PCT from variegate porphyria. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. The presence of an inherited deficiency of UROD can be demonstrated by measuring the enzyme in red blood cells and is present in about 20% of patients with PCT.
Treatment and Prognosis: PCT is the most treatable of the porphyrias. Treatment seems to be equally effective in familial and non-familial PCT. Factors that tend to activate the disease should be removed. The most widely recommended treatment is a schedule of repeated phlebotomy (removal of blood), with the aim of reducing iron in the liver. This actually reduces iron stores throughout the body. Usually, removal of only 5 to 6 pints of blood (one pint every one to two weeks) is sufficient, which indicates that iron stores are not excessively increased in most PCT patients. The best guides to response are measurements of serum ferritin and plasma porphyrins. Phlebotomies are stopped when the ferritin falls to ~20ng/ml. Another treatment approach is a regimen of low doses of either chloroquine (125mg twice weekly) or hydroxychloroquine (100mg twice weekly). Usual dosages of these drugs should not be used because they can cause transient but sometimes severe liver damage and worsening of photosensitivity in PCT patients. Recurrences can be treated in the same manner. But PCT does not usually recur after treatment. It is not necessary to continue phlebotomies after a remission has been achieved.
Hepatoerythropoietic Porphyria (HEP)
This very rare type of porphyria is also due to a deficiency of uroporphyrinogen decarboxylase. The enzyme deficiency is inherited as an autosomal recessive trait. The manifestations of HEP resemble CEP, with symptoms of skin blistering usually beginning in infancy. Porphyrins are increased in bone marrow and red blood cells, in contrast to PCT, as well as liver, plasma, urine and feces.
Hereditary Coproporphyria (HCP)
This is an autosomal dominant form of hepatic porphyria that is similar to AIP, except that some patients develop skin photosensitivity. The deficient enzyme is coproporphyrinogen oxidase. The diagnosis is established by finding excess coproporphyrin (especially coproporphyrin type III) in urine and stool. Other types of porphyrins show little or no increase. Urinary ALA and PBG are increased during acute attacks but may become normal on recovery. Reliable assays for the deficient enzyme are not generally available. If the enzyme is measured, red blood cells should not be used. The enzyme is found in mitochondria which are not present in red blood cells. Precautions and treatment for acute attacks are as described for AIP.
Variegate Porphyria (VP)
This form of hepatic porphyria is most common in the South African white population. It is less frequent elsewhere. It is an autosomal dominant disorder and may produce acute attacks (as in AIP) as well as skin photosensitivity. The deficient enzyme is protoporphyrinogen oxidase. The diagnosis is made by finding excess coproporphyrin in urine and both coproporphyrin and protoporphyrin in feces. The most sensitive screening test for VP is probably a plasma porphyrin assay. In patients with skin manifestations, it is important to distinguish VP or HCP from PCT, because treatment by phlebotomy or low-dose chloroquine is not successful in VP and HCP. Acute attacks are managed and may be prevented as in AIP
Erythropoietic Protoporphyria (EPP) or Protoporphyria
This porphyria is due to a deficiency of ferrochelatase. It is inherited as an autosomal dominant trait. Many different mutations of the ferrochelatase gene have been found in various EPP families. Protoporphyrin accumulates in the bone marrow, red blood cells and sometimes the liver. Excess protoporphyrin is excreted by the liver into the bile, after which it enters the intestine and is excreted in the feces. Urinary porphyrins are normal. The diagnosis is established by finding increased protoporphyrin in plasma, feces and red blood cells.
Symptoms: Swelling, burning, itching, and redness of the skin may appear during or immediately after exposure to sunlight, including sunlight that passes through window glass. Usually, these subside in 12 to 24 hours and heal without significant scarring or discoloration of the skin. Occasionally, the skin problems occur only after extended sunlight exposure. The skin lesions may progress to a chronic stage persisting for weeks and healing with superficial scars. However, blistering and scarring is less common than in other types of "cutaneous" porphyria. Skin manifestations generally begin during childhood. They are more severe in the summer and can recur throughout life. Other manifestations may include gallstones containing protoporphyrin, and occasionally, severe liver complications. Some carriers of the gene for EPP have no symptoms and may even have normal porphyrin levels.
Treatment and Prognosis: Treatment with beta-carotene improves sunlight tolerance but does not lower porphyrin levels. Lumitene (Tishcon, Inc.) is the only pharmaceutical grade beta-carotene preparation recommended for treatment of EPP. Cholestyramine ingestion may lower porphyrin levels in some patients.
Patients with EPP may develop excess deposition of protoporphyrin in the liver which can progress to scarring and liver failure. Fortunately, this seldom occurs.
EPP is generally not associated with neurological problems. However, a few patients with EPP and advanced liver damage have developed neurological symptoms similar to those in the "acute" porphyrias. To avoid liver complications, it is a good idea to avoid drugs that are impair bile flow (cholestasis), including estrogens and alcohol. Some patients with EPP report that drinking alcoholic beverages increases their photosensitivity.
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