Porphyrias

Definition

The porphyrias are disorders in which the body produces too much porphyrin and insufficient heme (an iron-containing nonprotein portion of the hemoglobin molecule). Porphyrin is a foundation structure for heme and certain enzymes. Excess porphyrins are excreted as waste in the urine and stool. Overproduction and overexcretion of porphyrins causes low, unhealthy levels of heme and certain important enzymes, creating various physical symptoms.

Description

Biosynthesis of heme is a multistep process that begins with simple molecules and ends with a large, complex heme molecule. Each step of the chemical pathway is directed by its own task-specific protein, called an enzyme. As a heme precursor molecule moves through each step, an enzyme modifies the precursor in some way. If a precursor molecule is not modified, it cannot proceed to the next step, causing a buildup of that specific precursor.

This situation is the main characteristic of the porphyrias. Owing to a defect in one of the enzymes of the heme biosynthesis pathway, protoporphyrins or porphyrins (heme precursors) are prevented from proceeding further along the pathway. These precursors accumulate at the stage of the enzyme defect causing an array of physical symptoms in an affected person. Specific symptoms depend on the point at which heme biosynthesis is blocked and which precursors accumulate. In general, the porphyrias primarily affect the skin and the nervous system. Symptoms can be debilitating or life threatening in some cases. Porphyria is most commonly an inherited condition. It can also, however, be acquired after exposure to poisonous substances.

Heme

Heme is produced in several tissues in the body, but its primary biosynthesis sites are the liver and the bone marrow. Heme synthesis for immature red blood cells, namely the erythroblasts and the reticulocytes, occurs in the bone marrow.

Although production is concentrated in the liver and bone marrow, heme is utilized in various capacities in virtually every tissue in the body. In most cells, heme is a key building block in the construction of factors that oversee metabolism and transport of oxygen and energy. In the liver, heme is a component of several vital enzymes, particularly cytochrome P450. Cytochrome P450 is involved in the metabolism of chemicals, vitamins, fatty acids, and hormones; it is very important in transforming toxic substances into easily excretable materials. In immature red blood cells, heme is the featured component of hemoglobin. Hemoglobin is the red pigment that gives red blood cells their characteristic color and their essential ability to transport oxygen.

Heme biosynthesis

The heme molecule is composed of porphyrin and an iron atom. Much of the heme biosynthesis pathway is dedicated to constructing the porphyrin molecule. Porphyrin is a large molecule shaped like a four-leaf clover. An iron atom is placed at its center point in the last step of heme biosynthesis.

The production of heme may be compared to a factory assembly line. At the start of the line, raw materials are fed into the process. At specific points along the line, an addition or adjustment is made to further development. Once additions and adjustments are complete, the final product rolls off the end of the line.

The heme "assembly line" is an eight-step process, requiring eight different and properly functioning enzymes:

1. delta-aminolevulinic acid synthase
2. delta-aminolevulinic acid dehydratase
3. porphobilogen deaminase
4. uroporphyrinogen III cosynthase
5. uroporphyrinogen decarboxylase
6. coproporphyrinogen oxidase
7. protoporphyrinogen oxidase
8. ferrochelatase

The control of heme biosynthesis is complex. Various chemical signals can trigger increased or decreased production. These signals can affect the enzymes themselves or the production of these enzymes, starting at the genetic level. For example, one point at which heme biosynthesis may be controlled is at the first step. When heme levels are low, greater quantities of delta-aminolevulinic acid (ALA) synthase are produced. As a result, larger quantities of heme precursors are fed into the biosynthesis pathway to step up heme production.

Porphyrias

Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a glitch in the biosynthesis pathway—represented by a defective enzyme—means that heme biosynthesis does not reach completion. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to correct the heme deficit.

The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds with a specific enzyme defect and an accumulation of the associated precursor. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a defect in ALA synthase activity does not have a corresponding porphyria.

Enzymes involved in heme biosynthesis display subtle, tissue-specific variations; therefore, heme biosynthesis may be impeded in the liver, but normal in the immature red blood cells, or vice versa. Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relative to other types. All porphyrias are considered to be rare disorders.

In the past, the porphyrias were divided into two general categories based on the location of the porphyrin production. Porphyrias affecting heme biosynthesis in the liver were referred to as hepatic porphyrias. Porphyrias that affect heme biosynthesis in immature red blood cells were referred to as erythropoietic porphyrias (erythropoiesis is the process through which red blood cells are produced). As of 2001, porphyrias were usually grouped into acute and non-acute types. Acute porphyrias produce severe attacks of pain and neurological effects. Non-acute porphyrias present as chronic diseases.

The acute porphyrias, and the heme biosynthesis steps at which enzyme defects occur, are:

• ALA dehydratase deficiency porphyria (step 2). This porphyria type is very rare. The inheritance pattern appears to be autosomal recessive. In autosomal recessively inherited disorders, a person must inherit two defective genes, one from each parent. A parent with only one gene for an autosomal recessive disorder does not display symptoms of the disease.
• Acute intermittent porphyria (step 3). Acute intermittent porphyria (AIP) is also known as Swedish porphyria, pyrroloporphyria, and intermittent acute porphyria. AIP is inherited as an autosomal dominant trait, which means that only one copy of the defective gene needs to be present for the disorder to occur. Simply inheriting this gene, however, does not necessarily mean that a person will develop the disease. Approximately five to 10 per 100,000 people in the United States carry a gene for AIP, but only 10% of these people ever develop symptoms of the disease.
• Hereditary coproporphyria (step 6). Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner. As with all porphyrias, it is an uncommon ailment. By 1977, only 111 cases of HCP were recorded; in Denmark, the estimated incidence is two in one million people.
• Variegate porphyria (step 7). Variegate porphyria (VP) is also known as porphyria variegata, protocoproporphyria, South African genetic porphyria, and Royal malady (supposedly King George III of England and Mary, Queen of Scots, suffered from VP). VP is inherited in an autosomal dominant manner and is especially prominent in South Africans of Dutch descent. Among that population, the incidence is approximately three in 1,000 persons. It is estimated that there are 10,000 cases of VP in South Africa. Interestingly, it appears that the affected South Africans are descendants of two Dutch settlers who came to South Africa in 1680. Among other populations, the incidence of VP is estimated to be one to two cases per 100,000 persons.

The non-acute porphyrias, and the steps of heme biosynthesis at which they occur, are:

• Congenital erythropoietic porphyria (step 4). Congenital erythropoietic porphyria (CEP) is also called Gunther's disease, erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria. CEP is inherited in an autosomal recessive manner. It is a rare disease, estimated to affect fewer than one in one million people. Onset of dramatic symptoms usually occurs in infancy, but may hold off until adulthood.
• Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C ), drug or alcohol use, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, however most people remain latent—that is, symptoms never develop. PCT is the most common of the porphyrias, but the incidence of PCT is not well defined.
• Hepatoerythopoietic porphyria (step 5). Hepatoerythopoietic porphyria (HEP) affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), and is caused by defects in the same gene as PCT. Disease symptoms, however, strongly resemble congenital erythropoietic porphyria. HEP seems to be inherited in an autosomal recessive manner.
• Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, onset of symptoms typically occurred in childhood.

Causes and symptoms

General characteristics

The underlying cause of all porphyrias is a defective enzyme important to the heme biosynthesis pathway. Porphyrias are inheritable conditions. In virtually all cases of porphyria an inherited factor causes the enzyme's defect. An environmental trigger—such as diet, drugs, or sun exposure—may be necessary before any symptoms develop. In many cases, symptoms do not develop. These asymptomatic individuals may be completely unaware that they have a gene for porphyria.

All of the hepatic porphyrias—except porphyria cutanea tarda—follow a pattern of acute attacks separated by periods during which no symptoms are present. For this reason, this group is often referred to as the acute porphyrias. The erythropoietic porphyrias and porphyria cutanea tarda do not follow this pattern and are considered to be chronic conditions.

The specific symptoms of each porphyria vary based on which enzyme is affected and whether that enzyme occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same type of porphyria. If the porphyria becomes symptomatic, the common factor between all types is an abnormal accumulation of protoporphyrins or porphyrin.

ALA dehydratase porphyria (ADP)

ADP is characterized by a deficiency of ALA dehydratase. ADP is caused by mutations in the delta-aminolevulinate dehydratase gene (ALAD) at 9q34. Of the few cases on record, the prominent symptoms are vomiting, pain in the abdomen, arms, and legs, and neuropathy. (Neuropathy refers to nerve damage that can cause pain, numbness, or paralysis.) The nerve damage associated with ADP could cause breathing impairment or lead to weakness or paralysis of the arms and legs.

Acute intermittent porphyria (AIP)

AIP is caused by a deficiency of porphobilogen deaminase, which occurs due to mutations in the hydroxymethylbilane synthase gene (HMBS) located at 11q23.3. Symptoms of AIP usually do not occur unless a person with the deficiency encounters a trigger substance. Trigger substances can include hormones (for example oral contraceptives, menstruation, pregnancy ), drugs, and dietary factors. Most people with this deficiency never develop symptoms.

Attacks occur after puberty and commonly feature severe abdominal pain, nausea, vomiting, and constipation. Muscle weakness and pain in the back, arms, and legs are also typical symptoms. During an attack, the urine is a deep reddish color. The central nervous system may also be involved. Possible psychological symptoms include hallucinations, confusion, seizures, and mood changes.

Congenital erythropoietic porphyria (CEP)

CEP is caused by a deficiency of uroporphyrinogen III cosynthase due to mutations in the uroporphyrinogen III cosynthase gene (UROS) located at 10q25.2-q26.3. Symptoms are often apparent in infancy and include reddish urine and possibly an enlarged spleen. The skin is unusually sensitive to light and blisters easily if exposed to sunlight. (Sunlight induces protoporphyrin changes in the plasma and skin. These altered protoporphyrin molecules can cause skin damage.) Increased hair growth is common. Damage from recurrent blistering and associated skin infections can be severe. In some cases facial features and fingers may be lost to recurrent damage and infection. Deposits of protoporphyrins can sometimes lead to red staining of the teeth and bones.

Porphyria cutanea tarda (PCT)

PCT is caused by deficient uroporphyrinogen decarboxylase. PCT is caused by mutations in the uroporphyrinogen decarboxylase gene (UROD) located at 1p34. PCT may occur as an acquired or an inherited condition. The acquired form usually does not appear until adulthood. The inherited form may appear in childhood, but often demonstrates no symptoms. Early symptoms include blistering on the hands, face, and arms following minor injuries or exposure to sunlight. Lightening or darkening of the skin may occur along with increased hair growth or loss of hair. Liver function is abnormal but the signs are mild.

Hepatoerythopoietic porphyria (HEP)

HEP is linked to a deficiency of uroporphyrinogen decarboxylase in both the liver and the bone marrow. HEP is an autosomal recessive disease caused by mutations in the gene responsible for PCT, the uroporphyrinogen decarboxylase gene (UROD), located at 1p34. The gene is shared, but the mutations, inheritance, and specific symptoms of these two diseases are different. The symptoms of HEP resemble those of CEP.

Hereditary coproporphyria (HCP)

HCP is similar to AIP, but the symptoms are typically milder. HCP is caused by a deficiency of coproporphyrinogen oxidase due to mutations in a gene by the same name at 3q12. The greatest difference between HCP and AIP is that people with HCP may have some skin sensitivity to sunlight. However, extensive damage to the skin is rarely seen.

Variegate porphyria (VP)

VP is caused by a deficiency of protoporphyrinogen oxidase. There is scientific evidence that VP is caused by mutation in the gene for protoporphyrinogen oxidase located at 1q22. Like AIP, symptoms of VP occur only during attacks. Major symptoms of this type of porphyria include neurological problems and sensitivity to light. Areas of the skin that are exposed to sunlight are susceptible to burning, blistering, and scarring.

Erythropoietic protoporphyria (EPP)

Owing to deficient ferrochelatase, the last step in the heme biosynthesis pathway—the insertion of an iron atom into a porphyrin molecule—cannot be completed. This enzyme deficiency is caused by mutations in the ferrochelatase gene (FECH) located at 18q21.3. The major symptoms of this disorder are related to sensitivity to light—including both artificial and natural light sources. Following exposure to light, a person with EPP experiences burning, itching, swelling, and reddening of the skin. Blistering and scarring may occur but are neither common nor severe. EPP is associated with increased risks for gallstones and liver complications. Symptoms can appear in childhood and tend to be more severe during the summer when exposure to sunlight is more likely.

Diagnosis

Depending on the array of symptoms an individual may exhibit, the possibility of porphyria may not immediately come to a physician's mind. In the absence of a family history of porphyria, non-specific symptoms, such as abdominal pain and vomiting, may be attributed to other disorders. Neurological symptoms, including confusion and hallucinations, can lead to an initial suspicion of psychiatric disease. Diagnosis is more easily accomplished in cases in which nonspecific symptoms appear in combination with symptoms more specific to porphyria, like neuropathy, sensitivity to sunlight, or certain other manifestations. Certain symptoms, such as urine the color of port wine, are hallmark signs very specific to porphyria. DNA analysis is not yet of routine diagnostic value.

A common initial test measures protoporphyrins in the urine. However, if skin sensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are done to measure heme precursor levels in red blood cells and the stool. The presence and estimated quantity of porphyrin and protoporphyrins in biological samples are easily detected using spectrofluorometric testing. Spectrofluorometric testing uses a spectrofluorometer that directs light of a specific strength at a fluid sample. The porphyrins and protoporphyrins in the sample absorb the light energy and fluoresce, or glow. The spectrofluorometer detects and measures fluorescence, which indicates the amount of porphyrins and protoporphyrins in the sample.

Whether heme precursors occur in the blood, urine, or stool gives some indication of the type of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective; which, in turn, allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. For example, a screening test for acute intermittent porphyria (AIP) is the Watson-Schwartz test. In this test, a special dye is added to a urine sample. If one of two heme precursors—porphobilinogen or urobilinogen—is present, the sample turns pink or red. Further testing is necessary to determine whether the precursor present is porphobilinogen or urobilinogen—only porphobilinogen is indicative of AIP.

Other biochemical tests rely on the fact that heme precursors become less soluble in water (able to be dissolved in water) as they progress further through the heme biosynthesis pathway. For example, to determine whether the Watson-Schwartz urine test is positive for porphobilinogen or urobilinogen, chloroform is added to the test tube. Chloroform is a water-insoluble substance. Even after vigorous mixing, the water and chloroform separate into two distinct layers. Urobilinogen is slightly insoluble in water, while porphobilinogen tends to be water soluble. The porphobilinogen mixes more readily in water than chloroform, so if the water layer is pink (from the dye added to the urine sample), that indicates the presence of porphobilinogen, and a diagnosis of AIP is probable.

As a final test, measuring specific enzymes and their activities may be done for some types of porphyrias; however, such tests are not done as a screening method. Certain enzymes, such as porphobilinogen deaminase (the defective enzyme in AIP), can be easily extracted from red blood cells; other enzymes, however, are less readily collected or tested. Basically, an enzyme test involves adding a certain amount of the enzyme to a test tube that contains the precursor it is supposed to modify. Both the production of modified precursor and the rate at which it appears can be measured using laboratory equipment. If a modified precursor is produced, the test indicates that the enzyme is doing its job. The rate at which the modified precursor is produced can be compared to a standard to measure the efficiency of the enzyme.

Treatment

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. Treatment options vary depending on the specific type of porphyria diagnosed. Gene therapy has been successful for both CEP and EPP. In the future, scientists expect development of gene therapy for the remaining porphyrias. Given the rarity of ALA dehydratase porphyria, definitive treatment guidelines for this rare type have not been developed.

Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria

Treatment for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria follows the same basic regime. A person who has been diagnosed with one of these porphyrias can prevent most attacks by avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition, particularly with respect to carbohydrates. In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously. In 2004, a report from Turkey revealed successful treatment of an acute intermittent porphyria attack with a drug called fluoxetine.

When attacks occur prompt medical attention is necessary. Pain is usually severe, and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety, and chloral hydrate or diazepam is useful for sedation or to induce sleep. Hematin, a drug administered intravenously, may be used to halt an attack. Hematin seems to work by signaling the pathway of heme biosynthesis to slow production of precursors. Women, who tend to develop symptoms more frequently than men owing to hormonal fluctuations, may find ovulation-inhibiting hormone therapy to be helpful.

Gene therapy is a possible future treatment for these porphyrias. An experimental animal model of AIP has been developed and research is in progress.

Congenital erythropoietic porphyria

The key points of congenital erythropoietic porphyria treatment are avoiding exposure to sunlight and prevention of skin trauma or skin infection. Liberal use of sunscreens and consumption of betacarotene supplements can provide some protection from sun-induced damage. Medical treatments such as removing the spleen or administering transfusions of red blood cells can create short-term benefits, but these treatments do not offer a cure. Remission can sometimes be achieved after treatment with oral doses of activated charcoal. Severely affected patients may be offered bone marrow transplantation which appears to confer long-term benefit.

Porphyria cutanea tarda

As with other porphyrias, the first line of defense is avoidance of factors, especially alcohol, that could bring about symptoms. Regular blood withdrawal is a proven therapy for pushing symptoms into remission. If an individual is anemic or cannot have blood drawn for other reasons, chloroquine therapy may be used.

Erythropoietic protoporphyria

Avoiding sunlight, using sunscreens, and taking beta-carotene supplements are typical treatment options for erythropoietic protoporphyria. The drug cholestyramine may reduce the skin's sensitivity to sunlight as well as the accumulated heme precursors in the liver. Liver transplantation has been used in cases of liver failure. In 2004, a report in a medical journal told of one case of successful treatment of a 19-year-old patient with acute intermittent porphyria with liver transplantation. While she had only been studied for 1.5 years, the authors said her quality of life was good and they hoped that the procedure would offer cure for select patients with severe forms of the disease.

Alternative treatment

Acute porphyria attacks can be life-threatening events, so attempts at self-treatment can be dangerous. Alternative treatments can be useful adjuncts to conventional therapy. For example, some people may find relief for the pain associated with acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria through acupuncture or hypnosis. Relaxation techniques, such as yoga or meditation, may also prove helpful in pain management.

Prognosis

Even when porphyria is inherited, symptom development depends on a variety of factors. In the majority of cases, a person remains asymptomatic throughout life. About one percent of acute attacks can be fatal. Other symptoms may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, dangers associated with pregnancy as not as great as was once thought.

Prevention

For the most part, the porphyrias are attributable to inherited genes; such inheritance cannot be prevented. However, symptoms can be limited or prevented by avoiding factors that trigger symptom development.

People with a family history of an acute porphyria should be screened for the disease. Even if symptoms are absent, it is useful to know about the presence of the gene to assess the risks of developing the associated porphyria. This knowledge also reveals whether a person's offspring may be at risk. Prenatal testing for certain porphyrias is possible. Prenatal diagnosis of congenital erythropoietic porphyria has been successfully accomplished. Any prenatal tests, however, would not indicate whether a child would develop porphyria symptoms; only that the potential is there.

KEY TERMS

Autosomal dominant— A pattern of genetic inheritance in which only one abnormal gene is needed to display the trait or disease.

Autosomal recessive— A pattern of genetic inheritance in which two abnormal genes are needed to display the trait or disease.

Biosynthesis— The manufacture of materials in a biological system.

Bone marrow— A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.

Enzyme— A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Erythropoiesis— The process through which new red blood cells are created; it begins in the bone marrow.

Erythropoietic— Referring to the creation of new red blood cells.

Gene— A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found at a section of DNA. Each gene is found on a precise location on a chromosome.

Hematin— A drug administered intravenously to halt an acute porphyria attack. It causes heme biosynthesis to decrease, preventing the further accumulation of heme precursors.

Heme— The iron-containing molecule in hemoglobin that serves as the site for oxygen binding.

Hemoglobin— Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells.

Hepatic— Referring to the liver.

Neuropathy— A condition caused by nerve damage. Major symptoms include weakness, numbness, paralysis, or pain in the affected area.

Porphyrin— A large molecule shaped like a four-leaf clover. Combined with an iron atom, it forms a heme molecule.

Protoporphyrin— A precursor molecule to the porphyrin molecule.

Resources

BOOKS

Deats-O'Reilly, Diana. Porphyria: The Unknown Disease. Grand Forks, N.D.: Porphyrin Publications Press/Educational Services, 1999.

PERIODICALS

"Fluoxetine Treats Acute Intermittent Porphyria Safely and Effectively." Drug Week January 16, 2004: 292.

Gordon, Neal. "The Acute Porphyrias." Brain & Development 21 (September 1999): 373-77.

Thadani, Helen, et al. "Diagnosis and Management of Porphyria." British Medical Journal 320 (June 2000): 1647-51.

Zahir, Soonawalla F., et al. "Liver Transplantation as a Cure for Acute Intermittent Porphyria." The Lancet February 28, 2004: 705.

ORGANIZATIONS

American Porphyria Foundation. PO Box 22712, Houston, TX 77227. (713) 266-9617. 〈http://www.enterprise.net/apf/〉.

OTHER

Gene Clinics. 〈http://www.geneclinics.org〉.

National Institute of Diabetes & Digestive & Kidney Diseases. 〈http://www.niddk.nih.gov〉.

Online Mendelian Inheritance in Man (OMIM). 〈http://www3.ncbi.nlm.nih.gov/Omim〉.

Porphyrias

Definition

The porphyrias are disorders in which the body produces too much porphyrin and insufficient heme (an iron-containing nonprotein portion of the hemoglobin molecule). Porphyrin is a foundation structure for heme and certain enzymes. Excess porphyrins are excreted as waste in urine and stool. Overproduction and overexcretion of porphyrins causes low, unhealthy levels of heme and certain important enzymes, creating various physical symptoms.

Description

Biosynthesis of heme is a multistep process that begins with simple molecules and ends with a large, complex heme molecule. Each step of the chemical pathway is directed by its own task-specific protein, called an enzyme. As a heme precursor molecule moves through each step, an enzyme modifies the precursor in some way. If a precursor molecule is not modified, it cannot proceed to the next step, causing a buildup of that specific precursor.

This situation is the main characteristic of the porphyrias. Owing to a defect in one of the enzymes of the heme biosynthesis pathway, protoporphyrins or porphyrins (heme precursors) are prevented from proceeding further along the pathway. These precursors accumulate at the stage of the enzyme defect, causing an array of physical symptoms in an affected child. Specific symptoms depend on the point at which heme biosynthesis is blocked and which precursors accumulate. In general, the porphyrias primarily affect the skin and the nervous system. Symptoms can be debilitating or life threatening in some cases. Porphyria is most commonly an inherited condition. It can also, however, be acquired after exposure to poisonous substances.

Heme

Heme is produced in several tissues in the body, but its primary biosynthesis sites are the liver and the bone marrow. Heme synthesis for immature red blood cells, namely the erythroblasts and the reticulocytes, occurs in the bone marrow.

Although production is concentrated in the liver and bone marrow, heme is utilized in various capacities in virtually every tissue in the body. In most cells, heme is a key building block in the construction of factors that oversee metabolism and transport of oxygen and energy. In the liver, heme is a component of several vital enzymes, particularly cytochrome P450. Cytochrome P450 is involved in the metabolism of chemicals, vitamins , fatty acids, and hormones; it is very important in transforming toxic substances into easily excretable materials. In immature red blood cells, heme is the featured component of hemoglobin. Hemoglobin is the red pigment that gives red blood cells their characteristic color and their essential ability to transport oxygen.

Heme biosynthesis

The heme molecule is composed of porphyrin and an iron atom. Much of the heme biosynthesis pathway is dedicated to constructing the porphyrin molecule. Porphyrin is a large molecule shaped like a four-leaf clover. An iron atom is placed at its center point in the last step of heme biosynthesis.

The production of heme may be compared to a factory assembly line. At the start of the line, raw materials are fed into the process. At specific points along the line, an addition or adjustment is made to further development. Once additions and adjustments are complete, the final product rolls off the end of the line.

The heme "assembly line" is an eight-step process, requiring eight different and properly functioning enzymes:

1. delta-aminolevulinic acid synthase
2. delta-aminolevulinic acid dehydratase
3. porphobilogen deaminase
4. uroporphyrinogen III cosynthase
5. uroporphyrinogen decarboxylase
6. coproporphyrinogen oxidase
7. protoporphyrinogen oxidase
8. ferrochelatase

The control of heme biosynthesis is complex. Various chemical signals can trigger increased or decreased production. These signals can affect the enzymes themselves or the production of these enzymes, starting at the genetic level. For example, one point at which heme biosynthesis may be controlled is at the first step. When heme levels are low, greater quantities of delta-aminolevulinic acid (ALA) synthase are produced. As a result, larger quantities of heme precursors are fed into the biosynthesis pathway to step up heme production.

Porphyrias

Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a glitch in the biosynthesis pathway—represented by a defective enzyme—means that heme biosynthesis does not reach completion. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to correct the heme deficit.

The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds with a specific enzyme defect and an accumulation of the associated precursor. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a defect in ALA synthase activity does not have a corresponding porphyria.

Enzymes involved in heme biosynthesis display subtle, tissue-specific variations; therefore, heme biosynthesis may be impeded in the liver, but normal in the immature red blood cells, or vice versa. Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relative to other types. All porphyrias are considered to be rare disorders.

In the past, the porphyrias were divided into two general categories based on the location of the porphyrin production. Porphyrias affecting heme biosynthesis in the liver were referred to as hepatic porphyrias. Porphyrias that affect heme biosynthesis in immature red blood cells were referred to as erythropoietic porphyries. (Erythropoiesis is the process through which red blood cells are produced.) As of 2001, porphyrias are usually grouped into acute and non-acute types. Acute porphyrias produce severe attacks of pain and neurological effects. Non-acute porphyrias present as chronic diseases.

The acute porphyrias, and the heme biosynthesis steps at which enzyme defects occur, are:

• ALA dehydratase deficiency porphyria (step 2). This porphyria type is very rare. The inheritance pattern appears to be autosomal recessive. In autosomal recessively inherited disorders, a child must inherit two defective genes, one from each parent. A parent with only one gene for an autosomal recessive disorder does not display symptoms of the disease.
• Acute intermittent porphyria (step 3). Acute intermittent porphyria (AIP) is also known as Swedish porphyria, pyrroloporphyria, and intermittent acute porphyria. AIP is inherited as an autosomal dominant trait, which means that only one copy of the defective gene needs to be present for the disorder to occur. Simply inheriting this gene, however, does not necessarily mean that a child will develop the disease. Approximately five to 10 per 100,000 children in the United States carry a gene for AIP, but only 10 percent of these people, mostly teenage or older, ever develop symptoms of the disease.
• Hereditary coproporphyria (step 6). Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner. As with all porphyrias, it is an uncommon ailment. By 1977, only 111 cases of HCP were recorded; in Denmark, the estimated incidence is two in one million people.
• Variegate porphyria (step 7). Variegate porphyria (VP) is also known as porphyria variegata, protocoproporphyria, South African genetic porphyria, and Royal malady (supposedly King George III of England and Mary, Queen of Scots, suffered from VP). VP is inherited in an autosomal dominant manner and is especially prominent in South Africans of Dutch descent. Among that population, the incidence is approximately three in 1,000 persons. It is estimated that there are 10,000 cases of VP in South Africa. Interestingly, it appears that the affected South Africans are descendants of two Dutch settlers who came to South Africa in 1680. Among other populations, the incidence of VP is estimated to be one to two cases per 100,000 persons.

The non-acute porphyrias, and the steps of heme biosynthesis at which they occur, are:

• Congenital erythropoietic porphyria (step 4). Congenital erythropoietic porphyria (CEP) is also called Gunther's disease, erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria. CEP is inherited in an autosomal recessive manner. It is a rare disease, estimated to affect fewer than one in one million people. Onset of dramatic symptoms usually occurs in infancy, but may hold off until adulthood.
• Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C), drug or alcohol use, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, however most people remain latent—that is, symptoms never develop. PCT is the most common of the porphyrias, but the incidence of PCT is not well defined. However, PCT does not typically develop in children.
• Hepatoerythopoietic porphyria (step 5). Hepatoerythopoietic porphyria (HEP) affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), and is caused by defects in the same gene as PCT. Disease symptoms, however, strongly resemble congenital erythropoietic porphyria. HEP seems to be inherited in an autosomal recessive manner.
• Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, onset of symptoms typically occurred in childhood.

Causes and symptoms

General characteristics

The underlying cause of all porphyrias is a defective enzyme important to the heme biosynthesis pathway. Porphyrias are inheritable conditions. In virtually all cases of porphyria, an inherited factor causes the enzyme's defect. An environmental trigger—such as diet, drugs, or sun exposure—may be necessary before any symptoms develop. In many cases, symptoms do not develop. These asymptomatic individuals may be completely unaware that they have a gene for porphyria.

All of the hepatic porphyrias—except porphyria cutanea tarda—follow a pattern of acute attacks separated by periods during which no symptoms are present. For this reason, this group is often referred to as the acute porphyrias. The erythropoietic porphyrias and porphyria cutanea tarda do not follow this pattern and are considered to be chronic conditions.

The specific symptoms of each porphyria vary based on which enzyme is affected and whether that enzyme occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same type of porphyria. If the porphyria becomes symptomatic, the common factor between all types is an abnormal accumulation of protoporphyrins or porphyrin.

ALA dehydratase porphyria (ADP)

ADP is characterized by a deficiency of ALA dehydratase. ADP is caused by mutations in the delta-aminolevulinate dehydratase gene (ALAD) at 9q34. Being located at 9q34 means that it is on the long arm (q) of chromosome 9 in the 34 region. Of the few cases on record, the prominent symptoms are vomiting , pain in the abdomen, arms, and legs, and neuropathy. (Neuropathy refers to nerve damage that can cause pain, numbness , or paralysis.) The nerve damage associated with ADP could cause breathing impairment or lead to weakness or paralysis of the arms and legs.

Acute intermittent porphyria (AIP)

AIP is caused by a deficiency of porphobilinogen deaminase, which occurs due to mutations in the hydroxymethylbilane synthase gene (HMBS) located at 11q23.3. Symptoms of AIP usually do not occur unless a person with the deficiency encounters a trigger substance. Trigger substances can include hormones (for example oral contraceptives , menstruation , pregnancy), drugs, and dietary factors. Most people with this deficiency never develop symptoms.

Attacks occur after puberty and commonly feature severe abdominal pain, nausea , vomiting, and constipation . Muscle weakness and pain in the back, arms, and legs are also typical symptoms. During an attack, the urine is a deep reddish color. The central nervous system may also be involved. Possible psychological symptoms include hallucinations, confusion, seizures, and mood changes.

Congenital erythropoietic porphyria (CEP)

CEP is caused by a deficiency of uroporphyrinogen III cosynthase due to mutations in the uroporphyrinogen III cosynthase gene (UROS) located at 10q25.2-q26.3. Symptoms are often apparent in infancy and include reddish urine and possibly an enlarged spleen. The skin is unusually sensitive to light and blisters easily if exposed to sunlight. (Sunlight induces protoporphyrin changes in the plasma and skin. These altered protoporphyrin molecules can cause skin damage.) Increased hair growth is common. Damage from recurrent blistering and associated skin infections can be severe. In some cases facial features and fingers may be lost to recurrent damage and infection. Deposits of protoporphyrins can sometimes lead to red staining of the teeth and bones.

Porphyria cutanea tarda (PCT)

PCT is caused by deficient uroporphyrinogen decarboxylase. PCT is caused by mutations in the uroporphyrinogen decarboxylase gene (UROD) located at 1p34. PCT may occur as an acquired or an inherited condition. The acquired form usually does not appear until adulthood. The inherited form may appear in childhood, but often demonstrates no symptoms. Early symptoms include blistering on the hands, face, and arms following minor injuries or exposure to sunlight. Lightening or darkening of the skin may occur along with increased hair growth or loss of hair. Liver function is abnormal but the signs are mild.

Hepatoerythopoietic porphyria (HEP)

HEP is linked to a deficiency of uroporphyrinogen decarboxylase in both the liver and the bone marrow. HEP is an autosomal recessive disease caused by mutations in the gene responsible for PCT, the uroporphyrinogen decarboxylase gene (UROD), located at 1p34. The gene is shared, but the mutations, inheritance, and specific symptoms of these two diseases are different. The symptoms of HEP resemble those of CEP.

Hereditary coproporphyria (HCP)

HCP is similar to AIP, but the symptoms are typically milder. HCP is caused by a deficiency of coproporphyrinogen oxidase due to mutations in a gene by the same name at 3q12. The greatest difference between HCP and AIP is that people with HCP may have some skin sensitivity to sunlight. However, extensive damage to the skin is rarely seen.

Variegate porphyria (VP)

VP is caused by a deficiency of protoporphyrinogen oxidase. There is scientific evidence that VP is caused by mutation in the gene for protoporphyrinogen oxidase located at 1q22. Like AIP, symptoms of VP occur only during attacks. Major symptoms of this type of porphyria include neurological problems and sensitivity to light. Areas of the skin that are exposed to sunlight are susceptible to burning, blistering, and scarring.

Erythropoietic protoporphyria (EPP)

Owing to deficient ferrochelatase, the last step in the heme biosynthesis pathway—the insertion of an iron atom into a porphyrin molecule—cannot be completed. This enzyme deficiency is caused by mutations in the ferrochelatase gene (FECH) located at 18q21.3. The major symptoms of this disorder are related to sensitivity to light—including both artificial and natural light sources. Following exposure to light, a child with EPP experiences burning, itching , swelling, and reddening of the skin. Blistering and scarring may occur but are neither common nor severe. EPP is associated with increased risks for gallstones and liver complications. Symptoms can appear in childhood and tend to be more severe during the summer when exposure to sunlight is more likely.

Diagnosis

Depending on the array of symptoms a child may exhibit, the possibility of porphyria may not immediately come to a physician's mind. In the absence of a family history of porphyria, non-specific symptoms, such as abdominal pain and vomiting, may be attributed to other disorders. Neurological symptoms, including confusion and hallucinations, can lead to an initial suspicion of psychiatric disease. Diagnosis is more easily accomplished in cases in which non-specific symptoms appear in combination with symptoms more specific to porphyria, like neuropathy, sensitivity to sunlight, or certain other manifestations. Certain symptoms, such as urine the color of port wine, are hallmark signs very specific to porphyria. DNA analysis is not yet of routine diagnostic value.

A common initial test measures protoporphyrins in the urine. However, if skin sensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are done to measure heme precursor levels in red blood cells and the stool. The presence and estimated quantity of porphyrin and protoporphyrins in biological samples are easily detected using spectrofluorometric testing. Spectrofluorometric testing uses a spectrofluorometer that directs light of a specific strength at a fluid sample. The porphyrins and protoporphyrins in the sample absorb the light energy and fluoresce, or glow. The spectrofluorometer detects and measures fluorescence, which indicates the amount of porphyrins and protoporphyrins in the sample.

Whether heme precursors occur in the blood, urine, or stool gives some indication of the type of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective; which, in turn, allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. For example, a screening test for acute intermittent porphyria (AIP) is the Watson-Schwartz test. In this test, a special dye is added to a urine sample. If one of two heme precursors—porphobilinogen or urobilinogen—is present, the sample turns pink or red. Further testing is necessary to determine whether the precursor present is porphobilinogen or urobilinogen—only porphobilinogen is indicative of AIP.

Other biochemical tests rely on the fact that heme precursors become less soluble in water (able to be dissolved in water) as they progress further through the heme biosynthesis pathway. For example, to determine whether the Watson-Schwartz urine test is positive for porphobilinogen or urobilinogen, chloroform is added to the test tube. Chloroform is a water-insoluble substance. Even after vigorous mixing, the water and chloroform separate into two distinct layers. Urobilinogen is slightly insoluble in water, while porphobilinogen tends to be water-soluble. The porphobilinogen mixes more readily in water than chloroform, so if the water layer is pink (from the dye added to the urine sample), that indicates the presence of porphobilinogen, and a diagnosis of AIP is probable.

As a final test, measuring specific enzymes and their activities may be done for some types of porphyrias; however, such tests are not done as a screening method. Certain enzymes, such as porphobilinogen deaminase (the defective enzyme in AIP), can be easily extracted from red blood cells; other enzymes, however, are less readily collected or tested. Basically, an enzyme test involves adding a certain amount of the enzyme to a test tube that contains the precursor it is supposed to modify. Both the production of modified precursor and the rate at which it appears can be measured using laboratory equipment. If a modified precursor is produced, the test indicates that the enzyme is doing its job. The rate at which the modified precursor is produced can be compared to a standard to measure the efficiency of the enzyme.

Treatment

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. Treatment options vary depending on the specific type of porphyria diagnosed. Gene therapy has been successful for both CEP and EPP. In the future, scientists expect development of gene therapy for the remaining porphyrias. Given the rarity of ALA dehydratase porphyria, definitive treatment guidelines for this rare type have not been developed.

Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria

Treatment for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria follows the same basic regime. A child who has been diagnosed with one of these porphyrias can prevent most attacks by avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition , particularly with respect to carbohydrates. In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously.

When attacks occur prompt medical attention is necessary. Pain is usually severe, and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety , and chloral hydrate or diazepam is useful for sedation or to induce sleep . Hematin, a drug administered intravenously, may be used to halt an attack. Hematin seems to work by signaling the pathway of heme biosynthesis to slow production of precursors. Older girls, who tend to develop symptoms more frequently than boys owing to hormonal fluctuations, may find ovulation-inhibiting hormone therapy to be helpful.

Gene therapy is a possible future treatment for these porphyrias. An experimental animal model of AIP has been developed and research is in progress.

Congenital erythropoietic porphyria

The key points of congenital erythropoietic porphyria treatment are avoiding exposure to sunlight and prevention of skin trauma or skin infection. Liberal use of sunscreens and consumption of beta-carotene supplements can provide some protection from sun-induced damage. Medical treatments such as removing the spleen or administering transfusions of red blood cells can create short-term benefits, but these treatments do not offer a cure. Remission can sometimes be achieved after treatment with oral doses of activated charcoal. Severely affected patients may be offered bone marrow transplantation which appears to confer long-term benefit.

Porphyria cutanea tarda

As with other porphyrias, the first line of defense is avoidance of factors, especially alcohol, that could bring about symptoms. Regular blood withdrawal is a proven therapy for pushing symptoms into remission. If an individual is anemic or cannot have blood drawn for other reasons, chloroquine therapy may be used.

Erythropoietic protoporphyria

Avoiding sunlight, using sunscreens, and taking beta-carotene supplements are typical treatment options for erythropoietic protoporphyria. The drug cholestyramine may reduce the skin's sensitivity to sunlight as well as the accumulated heme precursors in the liver. Liver transplantation has been used in cases of liver failure, but it has not effected a long-term cure of the porphyria.

Alternative treatment

Acute porphyria attacks can be life-threatening events, so attempts at self-treatment can be dangerous. Alternative treatments can be useful adjuncts to conventional therapy. For example, some people may find relief for the pain associated with acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria through acupuncture or hypnosis. Relaxation techniques, such as yoga or meditation, may also prove helpful in pain management .

Prognosis

Even when porphyria is inherited, symptom development depends on a variety of factors. In the majority of cases, a person remains asymptomatic throughout life. About 1 percent of acute attacks can be fatal. Other symptoms may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, dangers associated with pregnancy as not as great as was once thought.

Prevention

For the most part, the porphyrias are attributable to inherited genes; such inheritance cannot be prevented. However, symptoms can be limited or prevented by avoiding factors that trigger symptom development.

Children with a family history of an acute porphyria should be screened for the disease. Even if symptoms are absent, it is useful to know about the presence of the gene to assess the risks of developing the associated porphyria. This knowledge also reveals whether a person's offspring may be at risk. Prenatal testing for certain porphyrias is possible. Prenatal diagnosis of congenital erythropoietic porphyria has been successfully accomplished. Any prenatal tests, however, would not indicate whether a child would develop porphyria symptoms; only that the potential is there.

Parental concerns

Many children with porphyria do not have symptoms. Many acute attacks can be prevented by knowing what causes the attacks, and avoiding those things in the diet or environment that result in acute attacks.

KEY TERMS

Autosomal dominant —A pattern of inheritance in which only one of the two copies of an autosomal gene must be abnormal for a genetic condition or disease to occur. An autosomal gene is a gene that is located on one of the autosomes or non-sex chromosomes. A person with an autosomal dominant disorder has a 50 percent chance of passing it to each of their offspring.

Autosomal recessive —A pattern of inheritance in which both copies of an autosomal gene must be abnormal for a genetic condition or disease to occur. An autosomal gene is a gene that is located on one of the autosomes or non-sex chromosomes. When both parents have one abnormal copy of the same gene, they have a 25 percent chance with each pregnancy that their offspring will have the disorder.

Biosynthesis —The manufacture of materials in a biological system.

Bone marrow —The spongy tissue inside the large bones in the body that is responsible for making the red blood cells, most white blood cells, and platelets.

Chromosome —A microscopic thread-like structure found within each cell of the human body and consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Chromosomes contain the genetic information necessary to direct the development and functioning of all cells and systems in the body. They pass on hereditary traits from parents to child (like eye color) and determine whether the child will be male or female.

Enzyme —A protein that catalyzes a biochemical reaction without changing its own structure or function.

Erythropoiesis —The process through which new red blood cells are created; it begins in the bone marrow.

Erythropoietic —Referring to the creation of new red blood cells.

Gene —A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Hematin —A drug administered intravenously to halt an acute porphyria attack. It causes heme biosynthesis to decrease, preventing the further accumulation of heme precursors.

Heme —The iron-containing molecule in hemoglobin that serves as the site for oxygen binding.

Hemoglobin —An iron-containing pigment of red blood cells composed of four amino acid chains (alpha, beta, gamma, delta) that delivers oxygen from the lungs to the cells of the body and carries carbon dioxide from the cells to the lungs.

Hepatic —Refers to the liver.

Neuropathy —A disease or abnormality of the peripheral nerves (the nerves outside the brain and spinal cord). Major symptoms include weakness, numbness, paralysis, or pain in the affected area.

Porphyrin —An organic compound found in living things that founds the foundation structure for hemoglobin, chlorophyll, and other respiratory pigments. In humans, porphyrins combine with iron to form hemes.

Protoporphyrin —A kind of porphyrin that links with iron to form the heme of hemoglobin.

When to call a doctor

Notify a doctor if the child appears to have an acute attack. Some signs and symptoms of an acute attack are: pain, red, burning or blistering skin, red urine, neurological changes, or psychological changes.

Resources

BOOKS

Deats-O'Reilly, Diana. Porphyria: The Unknown Disease. Grand Forks, N.D.: Porphyrin Publications Press/Educational Services, 1999.

PERIODICALS

Gordon, Neal. "The Acute Porphyrias." Brain & Development 21 (September 1999): 373–77.

Thadani, Helen et al. "Diagnosis and Management of Porphyria." British Medical Journal 320 (June 2000): 1647–51.

ORGANIZATIONS

American Porphyria Foundation. PO Box 22712, Houston, TX 77227. (713) 266-9617. <www.porphyriafoundation.com/>.

OTHER

Gene Clinics. Available online at <www.geneclinics.org>.

National Institute of Diabetes & Digestive & Kidney Diseases. Available online at <www.niddk.nih.gov>.

Online Mendelian Inheritance in Man (OMIM). Available online at <www3.ncbi.nlm.nih.gov/Omim>.

Mark A. Best Julia Barrett Judy C. Hawkins, MS

Porphyrias

Definition

The porphyrias are disorders in which the body produces too much porphyrin and insufficient heme (an iron-containing non-protein portion of the hemoglobin molecule). Porphyrin is a foundation structure for heme and certain enzymes. Excess porphyrins are excreted as waste in the urine and stool. Overproduction and overexcretion of porphyrins causes low, unhealthy levels of heme and certain important enzymes creating various physical symptoms.

Description

Biosynthesis of heme is a multistep process that begins with simple molecules and ends with a large, complex heme molecule. Each step of the chemical pathway is directed by its own task-specific protein, called an enzyme. As a heme precursor molecule moves through each step, an enzyme modifies the precursor in some way. If a precursor molecule is not modified, it cannot proceed to the next step, causing a build-up of that specific precursor.

This situation is the main characteristic of the porphyrias. Owing to a defect in one of the enzymes of the heme biosynthesis pathway, protoporphyrins or porphyrins (heme precursors) are prevented from proceeding further along the pathway. These precursors accumulate at the stage of the enzyme defect causing an array of physical symptoms in an affected person. Specific symptoms depend on the point at which heme biosynthesis is blocked and which precursors accumulate. In general, the porphyrias primarily affect the skin and the nervous system. Symptoms can be debilitating or life threatening in some cases. Porphyria is most commonly an inherited condition. It can also, however, be acquired after exposure to poisonous substances.

Heme

Heme is produced in several tissues in the body, but its primary biosynthesis sites are the liver and bone marrow. Heme synthesis for immature red blood cells, namely the erythroblasts and the reticulocytes, occurs in the bone marrow.

Although production is concentrated in the liver and bone marrow, heme is utilized in various capacities in virtually every tissue in the body. In most cells, heme is a key building block in the construction of factors that oversee metabolism and transport of oxygen and energy. In the liver, heme is a component of several vital enzymes, particularly cytochrome P450. Cytochrome P450 is involved in the metabolism of chemicals, vitamins, fatty acids, and hormones; it is very important in transforming toxic substances into easily excretable materials. In immature red blood cells, heme is the featured component of hemoglobin. Hemoglobin is the red pigment that gives red blood cells their characteristic color and their essential ability to transport oxygen.

Heme biosynthesis

The heme molecule is composed of porphyrin and an iron atom. Much of the heme biosynthesis pathway is dedicated to constructing the porphyrin molecule. Porphyrin is a large molecule shaped like a four-leaf clover. An iron atom is placed at its center point in the last step of heme biosynthesis.

The production of heme may be compared to a factory assembly line. At the start of the line, raw materials are fed into the process. At specific points along the line, an addition or adjustment is made to further development. Once additions and adjustments are complete, the final product rolls off the end of the line.

The heme "assembly line" is an eight-step process, requiring eight different and properly functioning enzymes:

• delta-aminolevulinic acid synthase
• delta-aminolevulinic acid dehydratase
• porphobilogen deaminase
• uroporphyrinogen III cosynthase
• uroporphyrinogen decarboxylase
• coproporphyrinogen oxidase
• protoporphyrinogen oxidase
• ferrochelatase

The control of heme biosynthesis is complex. Various chemical signals can trigger increased or decreased production. These signals can affect the enzymes themselves or the production of these enzymes, starting at the genetic level. For example, one point at which heme biosynthesis may be controlled is at the first step. When heme levels are low, greater quantities of delta-aminolevulinic acid (ALA) synthase are produced. As a result, larger quantities of heme precursors are fed into the biosynthesis pathway to step up heme production.

Porphyrias

Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a glitch in the biosynthesis pathway—represented by a defective enzyme—means that heme biosynthesis does not reach completion. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to correct the heme deficit.

The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds with a specific enzyme defect and an accumulation of the associated precursor. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a change in ALA synthase activity does not have a corresponding porphyria.

Enzymes involved in heme biosynthesis display subtle, tissue-specific variations; therefore, heme biosynthesis may be impeded in the liver, but normal in the immature red blood cells, or vice versa. Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relative to other types. All porphyrias are considered to be rare disorders.

In the past, the porphyrias were divided into two general categories based on the location of the porphyrin production. Porphyrias affecting heme biosynthesis in the liver were referred to as hepatic porphyrias. Porphyrias that affecting heme biosynthesis in immature red blood cells were referred to as erythropoietic porphyrias (erythropoiesis is the process through which red blood cells are produced). As of 2001, porphyrias are usually grouped into acute and non-acute types. Acute porphyrias produce severe attacks of pain and neurological effects. Nonacute porphyrias present as chronic diseases.

The acute porphyrias, and the heme biosynthesis steps at which enzyme problems occur, are:

• ALA dehydratase deficiency porphyria (step 2). This porphyria type is very rare. The inheritance pattern appears to be autosomal recessive. In autosomal recessively inherited disorders a person must inherit two defective genes, one from each parent. A parent with only one gene for an autosomal recessive disorder does not display symptoms of the disease.
• Acute intermittent porphyria (step 3). Acute intermittent porphyria (AIP) is also known as Swedish porphyria, pyrroloporphyria, and intermittent acute porphyria. AIP is inherited as an autosomal dominant trait, which means that only one copy of the abnormal gene needs to be present for the disorder to occur. Simply inheriting this gene, however, does not necessarily mean that a person will develop the disease. Approximately five to 10 per 100,000 persons in the United States carry a gene for AIP, but only 10% of these people ever develop symptoms of the disease.
• Hereditary coproporphyria (step 6). Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner. As with all porphyrias, it is an uncommon ailment. By 1977, only 111 cases of HCP were recorded; in Denmark, the estimated incidence is two in one million people.
• Variegate porphyria (step 7). Variegate porphyria (VP) is also known as porphyria variegata, protocoproporphyria, South African genetic porphyria, and Royal malady (supposedly King George III of England and Mary, Queen of Scots, had VP). VP is inherited in an autosomal dominant manner and is especially prominent in South Africans of Dutch descent. Among that population, the incidence is approximately three in 1,000 persons. It is estimated that there are 10,000 cases of VP in South Africa. Interestingly, it appears that the affected South Africans are descendants of two Dutch settlers who came to South Africa in 1680. Among other populations, the incidence of VP is estimated to be one to two cases per 100,000 persons.

The non-acute porphyrias, and the steps of heme biosynthesis at which they occur, are:

• Congenital erythropoietic porphyria (step 4). Congenital erythropoietic porphyria (CEP) is also called Gunther's disease, erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria. CEP is inherited in an autosomal recessive manner. It is a rare disease, estimated to affect less than one in one million people. Onset of dramatic symptoms usually occurs in infancy, but may hold off until adulthood.

• Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C), drug or alcohol use, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, however most people remain latent—that is, symptoms never develop. PCT is the most common of the porphyrias, but the incidence of PCT is not well defined.
• Hepatoerythopoietic porphyria (step 5). HEP affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), and is caused by changes in the same gene as PCT. Disease symptoms, however, strongly resemble congenital erythropoietic porphyria. HEP seems to be inherited in an autosomal recessive manner.
• Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, onset of symptoms typically occurred in childhood.

Causes and symptoms

General characteristics

The underlying cause of all porphyrias is an abnormal enzyme important to the heme biosynthesis pathway. Porphyrias are inheritable conditions. In virtually all cases of porphyria an inherited factor causes the enzyme's defect. An environmental trigger—such as diet, drugs, or sun exposure—may be necessary before any symptoms develop. In many cases, symptoms never develop. These asymptomatic individuals may be completely unaware that they have a gene for porphyria.

All of the hepatic porphyrias—except porphyria cutanea tarda—follow a pattern of acute attacks separated by periods in which no symptoms are present. For this reason, this group is often referred to as the acute porphyrias. The erythropoietic porphyrias and porphyria cutanea tarda do not follow this pattern and are considered to be chronic conditions.

The specific symptoms of each porphyria vary based on which enzyme is affected and whether that enzyme occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same type of porphyria. If the porphyria becomes symptomatic, the common factor between all types is an abnormal accumulation of protoporphyrins or porphyrin.

ALA dehydratase porphyria (ADP)

ADP is characterized by a deficiency of ALA dehydratase. ADP is caused by mutations in the delta-aminolevulinate dehydratase gene (ALAD) at 9q34. Of the few cases on record, the prominent symptoms were vomiting, pain in the abdomen, arms, and legs, and neuropathy. (Neuropathy refers to nerve damage that can cause pain, numbness, or paralysis.) The nerve damage associated with ADP could cause breathing impairment or lead to weakness or paralysis of the arms and legs.

Acute intermittent porphyria (AIP)

AIP is caused by a deficiency of porphobilogen deaminase, which occurs due to mutations in the hydroxymethylbilane synthase gene (HMBS) located at 11q23.3. Symptoms of AIP usually do not occur unless a person with the deficiency encounters a trigger substance. Trigger substances can include hormones (for example oral contraceptives, menstruation, pregnancy), drugs, and dietary factors. Most people with this deficiency never develop symptoms.

Attacks occur after puberty and commonly feature severe abdominal pain, nausea, vomiting, and constipation. Muscle weakness and pain in the back, arms, and legs are also typical symptoms. During an attack, the urine is a deep reddish color. The central nervous system may also be involved. Possible psychological symptoms include hallucinations, confusion, seizures, and mood changes.

Congenital erythropoietic porphyria (CEP)

CEP is caused by a deficiency of uroporphyrinogen III cosynthase due to mutations in the uroporphyrinogen III cosynthase gene (UROS) located at 10q25.2-q26.3. Symptoms are often apparent in infancy and include reddish urine and possibly an enlarged spleen. The skin is unusually sensitive to light and blisters easily if exposed to sunlight. (Sunlight induces protoporphyrin changes in the plasma and skin. These altered protoporphyrin molecules can cause skin damage.) Increased hair growth is common. Damage from recurrent blistering and associated skin infections can be severe. In some cases facial features and fingers may be lost to recurrent damage and infection. Deposits of protoporphyrins can sometimes lead to red staining of the teeth and bones.

Porphyria cutanea tarda (PCT)

PCT is caused by deficient uroporphyrinogen decarboxylase. PCT is caused by mutations in the uroporphyrinogen decarboxylase gene (UROD) located on chromosome 1 at 1p34. PCT may occur as an acquired or an inherited condition. The acquired form usually does not appear until adulthood. The inherited form may appear in childhood, but often demonstrates no symptoms. Early symptoms include blistering on the hands, face, and arms following minor injuries or exposure to sunlight. Lightening or darkening of the skin may occur along with increased hair growth or loss of hair. Liver function is abnormal but the signs are mild.

Hepatoerythopoietic porphyria (HEP)

HEP is linked to a deficiency of uroporphyrinogen decarboxylase in both the liver and the bone marrow. HEP is an autosomal recessive disease caused by mutations in the gene responsible for PCT, the uroporphyrinogen decarboxylase gene (UROD), located at 1p34. The gene is the shared, but the mutations, inheritance, and specific symptoms of these two diseases are different. The symptoms of HEP resemble those of CEP.

Hereditary coproporphyria (HCP)

HCP is similar to AIP, but the symptoms are typically milder. HCP is caused by a deficiency of coproporphyrinogen oxidase due to mutations in a gene by the same name at 3q12. The greatest difference between HCP and AIP is that people with HCP may have some skin sensitivity to sunlight. However, extensive damage to the skin is rarely seen.

Variegate porphyria (VP)

VP is caused by a deficiency of protoporphyrinogen oxidase. There is scientific evidence that VP is caused by a mutation in the gene for protoporphyrinogen oxidase located at 1q22. Like AIP, symptoms of VP occur only during attacks. Major symptoms of this type of porphyria include neurological problems and sensitivity to light. Areas of the skin that are exposed to sunlight are susceptible to burning, blistering, and scarring.

Erythropoietic protoporphyria (EPP)

Owing to deficient ferrochelatase, the last step in the heme biosynthesis pathway—the insertion of an iron atom into a porphyrin molecule—cannot be completed. This enzyme deficiency is caused by mutations in the ferrochelatase gene (FECH) located at 18q21.3. The major symptoms of this disorder are related to sensitivity to light—including both artificial and natural light sources. Following exposure to light, a person with EPP experiences burning, itching, swelling, and reddening of the skin. Blistering and scarring may occur but are neither common nor severe. EPP is associated with increased risks for gallstones and liver complications. Symptoms can appear in childhood and tend to be more severe during the summer when exposure to sunlight is more likely.

Diagnosis

Depending on the array of symptoms an individual may exhibit, the possibility of porphyria may not immediately come to a physician's mind. In the absence of a family history of porphyria, non-specific symptoms, such as abdominal pain and vomiting, may be attributed to other disorders. Neurological symptoms, including confusion and hallucinations, can lead to an initial suspicion of psychiatric disease. Diagnosis is more easily accomplished in cases in which non-specific symptoms appear in combination with symptoms more specific to porphyria, like neuropathy, sensitivity to sunlight, or certain other manifestations. Certain symptoms, such as urine the color of port wine, are hallmark signs very specific to porphyria. DNA analysis is not yet of routine diagnostic value.

A common initial test measures protoporphyrins in the urine. However, if skin sensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are done to measure heme precursor levels in red blood cells and the stool. The presence and estimated quantity of porphyrin and protoporphyrins in biological samples are easily detected using spectrofluorometric testing. Spectrofluorometric testing uses a spectrofluorometer that directs light of a specific strength at a fluid sample. The porphyrins and protoporphyrins in the sample absorb the light energy and fluoresce, or glow. The spectrofluorometer detects and measures fluorescence, which indicates the amount of porphyrins and protoporphyrins in the sample.

Whether heme precursors occur in the blood, urine, or stool gives some indication of the type of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective; which, in turn, allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. For example, a screening test for acute intermittent porphyria (AIP) is the Watson-Schwartz test. In this test, a special dye is added to a urine sample. If one of two heme precursors—porphobilinogen or urobilinogen—is present, the sample turns pink or red. Further testing is necessary to determine whether the precursor present is porphobilinogen or urobilinogen—only porphobilinogen is indicative of AIP.

Other biochemical tests rely on the fact that heme precursors become less soluble in water (able to be dissolved in water) as they progress further through the heme biosynthesis pathway. For example, to determine whether the Watson-Schwartz urine test is positive for porphobilinogen or urobilinogen, chloroform is added to the test tube. Chloroform is a water-insoluble substance. Even after vigorous mixing, the water and chloroform separate into two distinct layers. Urobilinogen is slightly insoluble in water, while porphobilinogen tends to be water-soluble. The porphobilinogen mixes more readily in water than chloroform, so if the water layer is pink (from the dye added to the urine sample), that indicates the presence of porphobilinogen, and a diagnosis of AIP is probable.

As a final test, measuring specific enzymes and their activities may be done for some types of porphyrias; however, such tests are not done as a screening method. Certain enzymes, such as porphobilinogen deaminase (the abnormal enzyme in AIP), can be easily extracted from red blood cells; other enzymes, however, are less readily collected or tested. Basically, an enzyme test involves adding a certain amount of the enzyme to a test tube that contains the precursor it is supposed to modify. Both the production of modified precursor and the rate at which it appears can be measured using laboratory equipment. If a modified precursor is produced, the test indicates that the enzyme is doing its job. The rate at which the modified precursor is produced can be compared to a standard to measure the efficiency of the enzyme.

Treatment and management

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. Treatment options vary depending on the specific type of porphyria diagnosed. Gene therapy has been successful for both CEP and EPP. In the future, scientists expect development of gene therapy for the remaining porphyrias. Given the rarity of ALA dehydratase porphyria, definitive treatment guidelines for this rare type have not been developed.

Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria

Treatment for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria follows the same basic regime. A person who has been diagnosed with one of these porphyrias can prevent most attacks by avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition, particularly in respect to carbohydrates. In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously.

When attacks occur, prompt medical attention is necessary. Pain is usually severe, and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety, and chloral hydrate or diazepam is useful for sedation or to induce sleep. Hematin, a drug administered intravenously, may be used to halt an attack. Hematin seems to work by signaling the pathway of heme biosynthesis to slow production of precursors. Women, who tend to develop symptoms more frequently than men owing to hormonal fluctuations, may find ovulation-inhibiting hormone therapy to be helpful.

Gene therapy is a possible future treatment for these porphyrias. An experimental animal model of AIP has been developed and research is in progress.

Congenital erythropoietic porphyria

The key points of congenital erythropoietic porphyria treatment are avoiding exposure to sunlight and prevention of skin trauma or skin infection. Liberal use of sunscreens and consumption of beta-carotene supplements can provide some protection from sun-induced damage. Medical treatments such as removing the spleen or administering transfusions of red blood cells can create short-term benefits, but these treatments do not offer a cure. Remission can sometimes be achieved after treatment with oral doses of activated charcoal. Severely affected patients may be offered bone marrow transplantation, which appears to confer long-term benefits.

Porphyria cutanea tarda

As with other porphyrias, the first line of defense is avoidance of factors, especially alcohol, that could bring about symptoms. Regular blood withdrawal is a proven therapy for pushing symptoms into remission. If an individual is anemic or cannot have blood drawn for other reasons, chloroquine therapy may be used.

Erythropoietic protoporphyria

Avoiding sunlight, using sunscreens, and taking beta-carotene supplements are typical treatment options for erythropoietic protoporphyria. The drug, cholestyramine, may reduce the skin's sensitivity to sunlight as well as the accumulated heme precursors in the liver. Liver transplantation has been used in cases of liver failure, but it has not effected a long-term cure of the porphyria.

Alternative treatment

Acute porphyria attacks can be life-threatening events, so attempts at self-treatment can be dangerous. Alternative treatments can be useful adjuncts to conventional therapy. For example, some people may find relief for the pain associated with acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria through acupuncture or hypnosis. Relaxation techniques, such as yoga or meditation, may also prove helpful in pain management.

Prognosis

Even when porphyria is inherited, symptom development depends on a variety of factors. In the majority of cases, a person remains asymptomatic throughout life. About one percent of acute attacks can be fatal. Other symptoms may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, dangers associated with pregnancy as not as great as was once thought.

Prevention

For the most part, the porphyrias are attributed to inherited genes; such inheritance cannot be prevented. However, symptoms can be limited or prevented by avoiding factors that trigger symptom development.

People with a family history of an acute porphyria should be screened for the disease. Even if symptoms are absent, it is useful to know about the presence of the gene to assess the risks of developing the associated porphyria. This knowledge also reveals whether a person's offspring may be at risk. Prenatal testing for certain porphyrias is possible. Prenatal diagnosis of congenital erythropoietic porphyria has been successfully accomplished. Any prenatal tests, however, would not indicate whether a child would develop porphyria symptoms; only that they might have the potential to do so.

Resources

BOOKS

Deats-O'Reilly, Diana. Porphyria: The Unknown Disease. Grand Forks, ND: Porphyrin Publications Press/Educational Services, 1999.

PERIODICALS

Gordon, Neal. "The Acute Porphyrias." Brain & Development 21 (September 1999): 373–77.

Thadani, Helen et al. "Diagnosis and Management of Porphyria." British Medical Journal 320 (June 2000): 1647–51.

ORGANIZATIONS

American Porphyria Foundation. PO Box 22712, Houston, TX 77227. (713) 266-9617. <http://www.enterprise.net/apf/>.

WEBSITES

Gene Clinics. <http://www.geneclinics.org>.

National Institute of Diabetes & Digestive & Kidney Diseases. <http://www.niddk.nih.gov>.

Online Mendelian Inheritance in Man (OMIM). <http://www3.ncbi.nlm.nih.gov/Omim>.

Julia Barrett

Judy Hawkins, MS

Porphyrias

Definition

The porphyrias are a group of rare disorders that affect heme biosynthesis. Heme is an essential component of hemoglobin as well as of many enzymes throughout the body.

Description

Biosynthesis of heme is a multistep process that starts with simple molecules and ends with a large, complex heme molecule. Each step of the biosynthesis pathway is directed by its own enzyme (a task-specific protein). As a heme precursor molecule moves through each step, an enzyme modifies it in some way. If the precursor is not modified, it cannot proceed to the next step.

The main characteristic of the porphyrias is a defect in one of the enzymes of the heme biosynthesis pathway. The defect prevents protoporphyrins or porphyrin (heme precursors) from proceeding further along the pathway. Symptoms may be debilitating or life-threatening in some cases. Porphyria is an inherited condition, but it may be acquired after exposure to poisonous substances.

Heme

Heme is primarily synthesized in the liver and bone marrow. Heme synthesis for immature red blood cells, namely the erythroblasts and the reticulocytes, occurs in the bone marrow.

Although production is concentrated in the liver and bone marrow, heme is used in various capacities in virtually every tissue in the body. In most cells, it is a key building block in the construction of factors that oversee metabolism as well as transport of oxygen and energy. In immature red blood cells, heme is a featured component of hemoglobin. Hemoglobin is the red pigment that gives red blood cells the ability to transport oxygen as well as their characteristic color.

Heme biosynthesis

The heme molecule is composed of porphyrin and an iron atom. Much of the heme biosynthesis pathway is dedicated to constructing the porphyrin molecule. Porphyrin is a large molecule shaped like a four-leaf clover. An iron atom is placed at its center during the last step of heme biosynthesis.

The production of heme may be compared to a factory assembly line. The heme "assembly line" is an eight-step process, requiring eight different—and properly functioning—enzymes:

• step 1: delta-aminolevulinic acid synthase
• step 2: delta-aminolevulinic acid dehydratase
• step 3: porphobilogen deaminase
• step 4: uroporphyrinogen III cosynthase
• step 5: uroporphyrinogen decarboxylase
• step 6: coproporphyrinogen oxidase
• step 7: protoporphyrinogen oxidase
• step 8: ferrochelatase

The control of heme biosynthesis is complex. There are various chemical signals that can trigger increased or decreased production. These signals can affect the enzymes themselves or their production, starting at the genetic level.

Porphyrias

Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a malfunction in the biosynthesis pathway—represented by a defective enzyme—means that heme biosynthesis does not reach completion. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to make up the deficit.

The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds to a specific enzyme defect and an accumulation of the associated precursor. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a defect in ALA synthase activity does not have a corresponding porphyria.

The porphyrias are divided into two general categories, depending on the location of the deficient enzyme. Porphyrias that affect heme biosynthesis in the liver are called hepatic porphyrias. The porphyrias that affect heme biosynthesis in immature red blood cells are called erythropoietic porphyrias (erythropoiesis is the process through which red blood cells are produced).

Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relative to other types; all porphyrias are considered rare disorders.

The hepatic porphyrias, and the heme biosynthesis steps at which enzyme defects occur, are:

• ALA dehydratase deficiency porphyria (step 2). This porphyria type is extraordinarily rare; only six cases have ever been reported in the medical literature. The inheritance pattern seems to be autosomal recessive, which means a defective enzyme gene must be inherited from both parents for the disorder to occur.
• Acute intermittent porphyria (step 3). Acute intermittent porphyria (AIP) is also known as Swedish porphyria, pyrroloporphyria, and intermittent acute porphyria. AIP is inherited as an autosomal dominant trait, which means only one copy of the defective gene needs to be present for the disorder to occur. However, simply inheriting this gene does not necessarily mean that a person will develop the disease. Approximately five to 10 per 100,000 persons in the United States carry the gene, but only 10% of carriers ever develop AIP symptoms.
• Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C), drug or alcohol abuse, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, but most people with the inherited form remain latent—that is, symptoms never develop. It is the most common of the porphyrias, but the incidence is not well defined.
• Hereditary coproporphyria (step 6). Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner. As with all porphyrias, it is an uncommon ailment. By 1977, only 111 cases were recorded; in Denmark, the estimated incidence is two in 1 million people.
• Variegate porphyria (step 7). Variegate porphyria (VP) is also known as porphyria variegata, protocoproporphyria, South African genetic porphyria, and royal malady (supposedly King George III of England and Mary, Queen of Scots, suffered from VP). VP is inherited in an autosomal dominant manner and is especially prominent in South Africans of Dutch descent. Among that population, the incidence is approximately three in 1,000 persons, and it is estimated that there are 10,000 cases of VP in South Africa. Interestingly, it seems that the affected South Africans are descendants of two Dutch settlers who came to South Africa in 1680. Elsewhere, the incidence is estimated to be one to two cases per 100,000 persons.

The erythropoietic porphyrias, and the steps of heme biosynthesis at which they occur, are:

• Congenital erythropoietic porphyria (step 4). Congenital erythropoietic porphyria (CEP) is also called Günther's disease, erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria. CEP is inherited in an autosomal recessive manner and occurs very rarely. Onset of symptoms usually occurs in infancy, but may be delayed until adulthood.
• Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, the onset of symptoms typically occurred in childhood.

In addition to the above types of porphyria, there is a very rare type, called hepatoerythopoietic porphyria (HEP), that affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), but strongly resembles congenital erythropoietic porphyria. Only 20 cases of HEP have been reported worldwide; it seems to be inherited in an autosomal recessive manner.

Causes and symptoms

General characteristics

The underlying cause of all porphyrias is a defective enzyme somewhere along the heme biosynthesis pathway. In virtually all cases, the defective enzyme is a genetically linked factor. Therefore, porphyrias are inheritable conditions. However, an environmental trigger—such as diet, drugs, or sun exposure—may be necessary before any symptoms develop. In many cases, symptoms do not develop, and individuals may be completely unaware that they have a gene for porphyria.

KEY TERMS

Autosomal dominant —An inheritance pattern in which a trait is determined by one gene in a pair (genes are inherited in pairs; one copy from each parent).

Autosomal recessive —An inheritance pattern in which a trait is expressed only if both genes in a pair code for that particular characteristic (genes are inherited in pairs; one copy from each parent).

Enzyme —A protein molecule that catalyzes a chemical reaction.

Erythropoiesis —The process through which new red blood cells are created; it begins in the bone marrow.

Erythropoietic —Referring to the creation of new red blood cells.

Gene —A portion of DNA (deoxyribonucleic acid) that codes for a specific product, such as an enzyme.

Hematin —A drug that is administered intravenously to halt an acute porphyria attack. It inhibits heme biosynthesis, preventing the further accumulation of heme precursors.

Heme —A large complex molecule contained in hemoglobin and a number of important enzymes throughout the body. Through these factors, it plays a vital role in metabolism and oxygen and energy transport. Heme is composed of porphyrin and an iron atom.

Hemoglobin —A molecule composed of heme and protein that enables red blood cells to transport oxygen throughout the body. Hemoglobin gives red blood cells their characteristic color.

Hepatic —Referring to the liver.

Neuropathy —A condition characterized by nerve damage. Major symptoms can include weakness, numbness, paralysis, or pain in the affected area.

Porphyrin —A large molecule shaped somewhat like a four-leaf clover. Combined with an iron atom, it forms a heme molecule.

Protoporphyrin —A precursor molecule to the porphyrin molecule.

All of the hepatic porphyrias—except porphyria cutanea tarda—follow a pattern of acute attacks interspersed with periods of complete symptom remission. For this reason, they are often referred to as the acute porphyrias. The erythropoietic porphyrias and porphyria cutanea tarda do not follow the same pattern and are considered chronic conditions.

The specific symptoms of each porphyria depend on the affected enzyme and whether it occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same porphyria type. When the porphyria becomes symptomatic, the common factor between all types is an abnormal accumulation of protoporphyrins or porphyrin.

ALA dehydratase porphyria (ADP)

ADP is characterized by a deficiency of ALA dehydratase. Of the few cases on record, the prominent symptoms were vomiting; pain in the abdomen, arms, and legs; and neuropathy. (Neuropathy refers to nerve damage that can cause pain, numbness, or paralysis.) As a result of neuropathy, the arms and legs may be weak or paralyzed and breathing can be impaired.

Acute intermittent porphyria (AIP)

AIP is caused by a deficiency in porphobilogen deaminase, but symptoms usually do not occur unless an individual with the deficiency encounters a biological trigger. Triggers can include hormones (for example oral contraceptives, menstruation, pregnancy ), drugs, and dietary factors. However, most people with the deficiency never develop symptoms.

Attacks occur after puberty and commonly feature severe abdominal pain, nausea and vomiting, and constipation. Muscle weakness and pain in the back, arms, and legs are also typical symptoms. During an attack, the urine takes on a deep reddish color. The central nervous system may also be involved, as demonstrated by hallucinations, confusion, seizures, and mood changes.

Congenital erythropoietic porphyria (CEP)

CEP arises from a deficiency in uroporphyrinogen III cosynthase. Symptoms are often apparent in infancy and include reddish urine and possibly an enlarged spleen. The skin is unusually sensitive to light and blisters easily if exposed to sunlight. (Sunlight induces changes in protoporphyrins in the plasma and skin. These altered molecules can damage the skin.) Increased hair growth is common. Damage from recurrent blistering and associated skin infections can be severe; in some cases facial features and fingers are lost to recurrent damage and infection . Deposits of protoporphyrins sometimes occur in the teeth and bones.

Porphyria cutanea tarda (PCT)

PCT is caused by deficient uroporphyrinogen decarboxylase; it may be an acquired or inherited condition. The acquired form usually does not appear until adulthood. The inherited form may appear in childhood, but often demonstrates no symptoms. Early symptoms include blistering on the hands, face, and arms following minor injuries or exposure to sunlight. Lightening or darkening of the skin may occur along with increased hair growth or loss of hair. Liver function is abnormal but the signs are mild.

Hepatoerythopoietic porphyria (HEP)

HEP is linked to a deficiency of uroporphyrinogen decarboxylase in both the liver and the bone marrow. The symptoms resemble those of CEP.

Hereditary coproporphyria (HCP)

HCP is similar to AIP, but the symptoms are typically milder; the disorder is caused by a deficiency in coproporphyrinogen oxidase. The greatest difference between HCP and AIP is that people with HCP may have some skin sensitivity to sunlight. However, extensive damage to the skin is rarely seen.

Variegate porphyria (VP)

VP is caused by deficient protoporphyrinogen oxidase, and, like AIP, symptoms only occur during attacks. Major symptoms of this type of porphyria involve neurologic problems and sensitivity to light. Areas of the skin that are exposed to sunlight are susceptible to burning, blistering, and scarring.

Erythropoietic protoporphyria (EPP)

Owing to deficient ferrochelatase, the last step in the heme biosynthesis pathway—the insertion of an iron atom into a porphyrin molecule—cannot be completed. The major symptoms of this disorder are related to sensitivity to light—including both artificial and natural light sources. Following exposure to light, a patient with EPP experiences burning, itching, swelling, and reddening of the skin. Blistering and scarring may occur but are neither common nor severe. EPP may result in the formation of gallstones as well as liver complications. Symptoms can appear in childhood and tend to be more severe during the summer when exposure to sunlight is more likely.

Diagnosis

Depending on the array of symptoms presented, the possibility of porphyria may not immediately come to the physician's mind. In the absence of a family history of porphyria, some symptoms of porphyria, such as abdominal pain and vomiting, may be attributed to other disorders. Neurological symptoms, including confusion and hallucinations, may lead to an initial suspicion of psychiatric illness rather than a physical disorder. Diagnosis may be aided in cases in which these symptoms appear in combination with neuropathy, sensitivity to sunlight, or other factors. Certain symptoms, such as urine the color of port wine, are hallmarks of porphyria.

A common initial test measures protoporphyrins in the urine. However, if skin sensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are performed to measure heme precursor levels in the stool and in red blood cells. The presence and estimated quantity of porphyrin and protoporphyrins are easily detected in biological samples using spectrofluorometric testing. This procedure involves the use of a laboratory instrument called a spectrofluorometer, which directs light of a specific strength at a fluid sample. Certain molecules in the sample—such as heme precursors—absorb the light energy and fluoresce. When molecules fluoresce, they emit light at a different strength from the absorbed light. The fluorescence can be detected and quantified by the spectrofluorometer. Not all molecules fluoresce, but among those that do, the intensity and quality of the fluorescence is an identifying characteristic. Diagnostic laboratory work, including analysis of blood, urine and stool samples is performed by laboratory technologists.

Heme precursors in the blood, urine, or stool give some indication of the type of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective, which in turn allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. For example, a screening test for acute intermittent porphyria (AIP) is the Watson-Schwartz test. In this test, a special dye is added to a urine sample. If one of two heme precursors—porphobilinogen or urobilinogen—is present, the sample turns pink or red. Further testing is necessary to determine whether the precursor is porphobilinogen or urobilinogen—only porphobilinogen is indicative of AIP.

Other biochemical tests rely on the fact that heme precursors become less water-soluble (able to be dissolved in water) as they progress further through the heme biosynthesis pathway. For example, to determine whether the Watson-Schwartz urine test is positive for porphobilinogen or urobilinogen, a measure of chloroform is added to the test tube. Chloroform is a water-insoluble substance, and even after vigorous mixing, the water and chloroform separate into two distinct layers. Whether the chloroform layer or the water layer becomes pink indicates which heme precursor is present. Porphobilinogen tends to be water-soluble, and urobilinogen is slightly water-insoluble. Since like mixes with like, porphobilinogen mixes more readily in the water than chloroform; therefore, if the water layer is pink, an AIP diagnosis is probable.

As a final test, measuring specific enzymes and their activities may be done for some types of porphyrias; however, such tests are not done for screening purposes. Certain enzymes, such as porphobilinogen deaminase (the defective enzyme in AIP), can be easily extracted from red blood cells; however, other enzymes are less readily collected or tested. Basically, an enzyme test involves adding a measure of the enzyme to a test tube containing the precursor it is supposed to modify. Both the production of modified precursor and the rate at which it appears are measured in the laboratory. If a modified precursor is produced, the test indicates that the enzyme is doing its job. The rate at which the modified precursor is produced can be compared to a standard to measure the enzyme's efficiency.

Treatment

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. However, treatment options vary depending on the type of porphyria that has been diagnosed. Given the rarity of ALA dehydratase porphyria (six reported cases), definitive treatment guidelines have not been developed.

Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria

Treatment for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria follows the same basic regime. A patient diagnosed with one of these porphyrias can prevent most attacks by avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition , particularly in respect to carbohydrates . In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously.

When an attack occurs, medical attention is needed. Pain is usually severe, and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety ; and chloral hydrate or diazepam is useful for sedation or to induce sleep. Intravenously administered hematin may be used to curtail an attack. This drug seems to work by signaling the heme biosynthesis pathway to slow production of precursors. Women, who tend to develop symptoms more frequently than men in response to hormonal fluctuations, may find hormone therapy that inhibits ovulation to be helpful.

Congenital erythropoietic porphyria

The key points of congenital erythropoietic porphyria treatment are avoiding exposure to sunlight, and preventing trauma to, and infections of the skin. Liberal use of sunscreens and taking beta-carotene supplements can provide some protection from sun-induced damage. Such medical treatments as removing the spleen or administering red blood cell transfusions can have short-term benefits, but do not offer a cure. Oral doses of activated charcoal may offer the potential of remission.

Porphyria cutanea tarda

As with other porphyrias, the first line of defense is the avoidance of precipitating factors, especially alcohol. Regular blood withdrawal is a proven therapy for pushing symptoms into remission. For patients who are anemic or cannot have blood drawn for other reasons, chloroquine therapy may be used.

Erythropoietic protoporphyria

Avoiding sunlight, using sunscreens, and taking beta-carotene supplements are typical treatment options for erythropoietic protoporphyria. The drug cholestyramine may reduce the skin's sensitivity to sunlight as well as the accumulated heme precursors in the liver. Liver transplantation has been used in cases of liver failure, but it has not effected a long-term cure of the porphyria.

Prognosis

Even in the presence of a genetic inheritance for a porphyria, symptom development depends on a variety of factors. In the majority of cases, an individual remains asymptomatic throughout life. Porphyria symptoms are rarely fatal with proper medical treatment, but they may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, it is not as great a danger as was once thought.

Health care team roles

Patients diagnosed with porphyrias are cared for by an interdisciplinary treatment team that may include primary care physicians, hematologists, and dermatologists. Laboratory technologists are involved during the diagnostic process; and nurses, health educators and genetic counselors provide instruction about how to recognize triggers and prevent attacks or flares of the condition.

Prevention

For the most part, the porphyrias are attributable to inherited genes; such an inheritance cannot be prevented. However, symptoms can be prevented or limited by avoiding factors that trigger development.

When there is a family history of porphyria, individuals should consider testing to determine whether they carry the associated gene. Even if symptoms are absent, it is useful to know about the presence of the gene to assess the risks of developing the associated porphyria. This knowledge also reveals whether the individual's offspring may be at risk. Theoretically, it is possible to perform prenatal tests. However, these tests would not indicate whether the child would develop porphyria symptoms; only that they might have the genetic predisposition to develop symptoms.

Resources

PERIODICALS

Fodinger, M., and Sunder-Plassman, G. "Inherited Disorders of Iron Metabolism." Kidney International Supplement 55, no. 69 (March 1999): S22-S34.

Murphy, G.M. "The Cutaneous Porphyrias: A Review." British Journal of Dermatology 140, no. 4 (April 1999): 573-581.

Nordmann, Y. et al. "The Porphyrias." Journal of Hepatology Supplement 30, no. 1 (1999): 12-16.

ORGANIZATIONS

American Porphyria Foundation. P.O. Box 22712, Houston, TX 77227. (713) 266-9617. <http://www.enterprise.net/apf/>.

Barbara Wexler

Porphyrias

Definition

The porphyrias are a group of rare disorders that affect heme biosynthesis. Heme is an essential component of hemoglobin as well as of many enzymes throughout the body.

Description

Biosynthesis of heme is a multistep process that starts with simple molecules and ends with a large, complex heme molecule. Each step of the biosynthesis pathway is directed by its own enzyme (a task-specific protein). As a heme precursor molecule moves through each step, an enzyme modifies it in some way. If the precursor is not modified, it cannot proceed to the next step.

The main characteristic of the porphyrias is a defect in one of the enzymes of the heme biosynthesis pathway. The defect prevents protoporphyrins or porphyrin (heme precursors) from proceeding further along the pathway. Symptoms may be debilitating or life-threatening in some cases. Porphyria is an inherited condition, but it may be acquired after exposure to poisonous substances.

Heme

Heme is primarily synthesized in the liver and bone marrow. Heme synthesis for immature red blood cells, namely the erythroblasts and the reticulocytes, occurs in the bone marrow.

Although production is concentrated in the liver and bone marrow, heme is used in various capacities in virtually every tissue in the body. In most cells, it is a key building block in the construction of factors that oversee metabolism as well as transport of oxygen and energy. In immature red blood cells, heme is a featured component of hemoglobin. Hemoglobin is the red pigment that gives red blood cells the ability to transport oxygen as well as their characteristic color.

Heme biosynthesis

The heme molecule is composed of porphyrin and an iron atom. Much of the heme biosynthesis pathway is dedicated to constructing the porphyrin molecule. Porphyrin is a large molecule shaped like a four-leaf clover. An iron atom is placed at its center during the last step of heme biosynthesis.

The production of heme may be compared to a factory assembly line. The heme "assembly line" is an eight-step process, requiring eight different—and properly functioning—enzymes:

• Step 1: delta-aminolevulinic acid synthase.
• Step 2: delta-aminolevulinic acid dehydratase.
• Step 3: porphobilogen deaminase.
• Step 4: uroporphyrinogen III cosynthase.
• Step 5: uroporphyrinogen decarboxylase.
• Step 6: coproporphyrinogen oxidase.
• Step 7: protoporphyrinogen oxidase.
• Step 8: ferrochelatase.

The control of heme biosynthesis is complex. There are various chemical signals that can trigger increased or decreased production. These signals can affect the enzymes themselves or their production, starting at the genetic level.

Porphyrias

Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a malfunction in the biosynthesis pathway—represented by a defective enzyme—means that heme biosynthesis does not reach completion. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to make up the deficit.

The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds to a specific enzyme defect and an accumulation of the associated precursor. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a defect in ALA synthase activity does not have a corresponding porphyria.

The porphyrias are divided into two general categories, depending on the location of the deficient enzyme. Porphyrias that affect heme biosynthesis in the liver are called hepatic porphyrias. The porphyrias that affect heme biosynthesis in immature red blood cells are called erythropoietic porphyrias. (Erythropoiesis is the process through which red blood cells are produced.)

Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relative to other types; all porphyrias are considered rare disorders.

The hepatic porphyrias, and the heme biosynthesis steps at which enzyme defects occur, are:

• ALA dehydratase deficiency porphyria (step 2). This porphyria type is extraordinarily rare; only six cases have ever been reported in the medical literature. The inheritance pattern seems to be autosomal recessive, which means a defective enzyme gene must be inherited from both parents for the disorder to occur.
• Acute intermittent porphyria (step 3). Acute intermittent porphyria (AIP) is also known as Swedish porphyria, pyrroloporphyria, and intermittent acute porphyria. AIP is inherited as an autosomal dominant trait, which means only one copy of the defective gene needs to be present for the disorder to occur. However, simply inheriting this gene does not necessarily mean that a person will develop the disease. Approximately five to 10 per 100,000 persons in the United States carry the gene, but only 10% of carriers ever develop AIP symptoms.
• Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C), drug or alcohol abuse, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, but most people with the inherited form remain latent—that is, symptoms never develop. It is the most common of the porphyrias, but the incidence is not well defined.
• Hereditary coproporphyria (step 6). Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner. As with all porphyrias, it is an uncommon ailment. By 1977, only 111 cases were recorded; in Denmark, the estimated incidence is two in 1 million people.
• Variegate porphyria (step 7). Variegate porphyria (VP) is also known as porphyria variegata, protocoproporphyria, South African genetic porphyria, and Royal malady (supposedly King George III of England and Mary, Queen of Scots, suffered from VP). VP is inherited in an autosomal dominant manner and is especially prominent in South Africans of Dutch descent. Among that population, the incidence is approximately three in 1,000 persons, and it is estimated that there are 10,000 cases of VP in South Africa. Interestingly, it seems that the affected South Africans are descendants of two Dutch settlers who came to South Africa in 1680. Elsewhere, the incidence is estimated to be one to two cases per 100,000 persons.

The erythropoietic porphyrias, and the steps of heme biosynthesis at which they occur, are:

• Congenital erythropoietic porphyria (step 4). Congenital erythropoietic porphyria (CEP) is also called Günther's disease, erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria. CEP is inherited in an autosomal recessive manner and occurs very rarely. Onset of symptoms usually occurs in infancy, but may be delayed until adulthood.
• Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, the onset of symptoms typically occurred in childhood.

In addition to the above types of porphyria, there is a very rare type, called hepatoerythopoietic porphyria (HEP), that affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), but strongly resembles congenital erythropoietic porphyria. Only 20 cases of HEP have been reported worldwide; it seems to be inherited in an autosomal recessive manner.

Causes and symptoms

General characteristics

The underlying cause of all porphyrias is a defective enzyme somewhere along the heme biosynthesis pathway. In virtually all cases, the defective enzyme is a genetically linked factor. Therefore, porphyrias are inheritable conditions. However, an environmental trigger—such as diet, drugs, or sun exposure—may be necessary before any symptoms develop. In many cases, symptoms do not develop, and individuals may be completely unaware that they have a gene for porphyria.

All of the hepatic porphyrias—except porphyria cutanea tarda—follow a pattern of acute attacks interspersed with periods of complete symptom remission. For this reason, they are often referred to as the acute porphyrias. The erythropoietic porphyrias and porphyria cutanea tarda do not follow the same pattern and are considered chronic conditions.

The specific symptoms of each porphyria depend on the affected enzyme and whether it occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same porphyria type. When the porphyria becomes symptomatic, the common factor between all types is an abnormal accumulation of protoporphyrins or porphyrin.

ALA dehydratase porphyria (ADP)

ADP is characterized by a deficiency of ALA dehydratase. Of the few cases on record, the prominent symptoms were vomiting; pain in the abdomen, arms, and legs; and neuropathy. (Neuropathy refers to nerve damage that can cause pain, numbness, or paralysis.) As a result of neuropathy, the arms and legs may be weak or paralyzed and breathing can be impaired.

Acute intermittent porphyria (AIP)

AIP is caused by a deficiency in porphobilogen deaminase, but symptoms usually do not occur unless an individual with the deficiency encounters a biological trigger. Triggers can include hormones (for example oral contraceptives, menstruation, pregnancy ), drugs, and dietary factors. However, most people with the deficiency never develop symptoms.

Attacks occur after puberty and commonly feature severe abdominal pain, nausea and vomiting, and constipation. Muscle weakness and pain in the back, arms, and legs are also typical symptoms. During an attack, the urine takes on a deep reddish color. The central nervous system may also be involved, as demonstrated by hallucinations, confusion, seizures, and mood changes.

Congenital erythropoietic porphyria (CEP)

CEP arises from a deficiency in uroporphyrinogen III cosynthase. Symptoms are often apparent in infancy and include reddish urine and possibly an enlarged spleen. The skin is unusually sensitive to light and blisters easily if exposed to sunlight. (Sunlight induces changes in protoporphyrins in the plasma and skin. These altered molecules can damage the skin.) Increased hair growth is common. Damage from recurrent blistering and associated skin infections can be severe; in some cases facial features and fingers are lost to recurrent damage and infection. Deposits of protoporphyrins sometimes occur in the teeth and bones.

Porphyria cutanea tarda (PCT)

PCT is caused by deficient uroporphyrinogen decarboxylase; it may be an acquired or inherited condition. The acquired form usually does not appear until adulthood. The inherited form may appear in childhood, but often demonstrates no symptoms. Early symptoms include blistering on the hands, face, and arms following minor injuries or exposure to sunlight. Lightening or darkening of the skin may occur along with increased hair growth or loss of hair. Liver function is abnormal but the signs are mild.

Hepatoerythopoietic porphyria (HEP)

HEP is linked to a deficiency of uroporphyrinogen decarboxylase in both the liver and the bone marrow. The symptoms resemble those of CEP.

Hereditary coproporphyria (HCP)

HCP is similar to AIP, but the symptoms are typically milder; the disorder is caused by a deficiency in coproporphyrinogen oxidase. The greatest difference between HCP and AIP is that people with HCP may have some skin sensitivity to sunlight. However, extensive damage to the skin is rarely seen.

Variegate porphyria (VP)

VP is caused by deficient protoporphyrinogen oxidase, and, like AIP, symptoms only occur during attacks. Major symptoms of this type of porphyria involve neurologic problems and sensitivity to light. Areas of the skin that are exposed to sunlight are susceptible to burning, blistering, and scarring.

Erythropoietic protoporphyria (EPP)

Owing to deficient ferrochelatase, the last step in the heme biosynthesis pathway—the insertion of an iron atom into a porphyrin molecule—cannot be completed. The major symptoms of this disorder are related to sensitivity to light—including both artificial and natural light sources. Following exposure to light, a patient with EPP experiences burning, itching, swelling, and reddening of the skin. Blistering and scarring may occur but are neither common nor severe. EPP may result in the formation of gallstones as well as liver complications. Symptoms can appear in childhood and tend to be more severe during the summer when exposure to sunlight is more likely.

Diagnosis

Depending on the array of symptoms presented, the possibility of porphyria may not immediately come to the physician's mind. In the absence of a family history of porphyria, some symptoms of porphyria, such as abdominal pain and vomiting, may be attributed to other disorders. Neurological symptoms, including confusion and hallucinations, may lead to an initial suspicion of psychiatric illness rather than a physical disorder. Diagnosis may be aided in cases in which these symptoms appear in combination with neuropathy, sensitivity to sunlight, or other factors. Certain symptoms, such as urine the color of port wine, are hallmarks of porphyria.

A common initial test measures protoporphyrins in the urine. However, if skin sensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are performed to measure heme precursor levels in the stool and in red blood cells. The presence and estimated quantity of porphyrin and protoporphyrins are easily detected in biological samples using spectrofluorometric testing. This procedure involves the use of a laboratory instrument called a spectrofluorometer, which directs light of a specific strength at a fluid sample. Certain molecules in the sample—such as heme precursors—absorb the light energy and fluoresce. When molecules fluoresce, they emit light at a different strength from the absorbed light. The fluorescence can be detected and quantified by the spectrofluorometer. Not all molecules fluoresce, but among those that do, the intensity and quality of the fluorescence is an identifying characteristic. Diagnostic laboratory work, including analysis of blood, urine and stool samples is performed by laboratory technologists.

Heme precursors in the blood, urine, or stool give some indication of the type of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective, which in turn allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. For example, a screening test for acute intermittent porphyria (AIP) is the Watson-Schwartz test. In this test, a special dye is added to a urine sample. If one of two heme precursors—porphobilinogen or urobilinogen—is present, the sample turns pink or red. Further testing is necessary to determine whether the precursor is porphobilinogen or urobilinogen—only porphobilinogen is indicative of AIP.

Other biochemical tests rely on the fact that heme precursors become less water soluble (able to be dissolved in water) as they progress further through the heme biosynthesis pathway. For example, to determine whether the Watson-Schwartz urine test is positive for porphobilinogen or urobilinogen, a measure of chloroform is added to the test tube. Chloroform is a water-insoluble substance, and even after vigorous mixing, the water and chloroform separate into two distinct layers. Whether the chloroform layer or the water layer becomes pink indicates which heme precursor is present. Porphobilinogen tends to be water soluble, and urobilinogen is slightly water insoluble. Since like mixes with like, porphobilinogen mixes more readily in the water than chloroform; therefore, if the water layer is pink, an AIP diagnosis is probable.

As a final test, measuring specific enzymes and their activities may be done for some types of porphyrias; however, such tests are not done for screening purposes. Certain enzymes, such as porphobilinogen deaminase (the defective enzyme in AIP), can be easily extracted from red blood cells; however, other enzymes are less readily collected or tested. Basically, an enzyme test involves adding a measure of the enzyme to a test tube containing the precursor it is supposed to modify. Both the production of modified precursor and the rate at which it appears are measured in the laboratory. If a modified precursor is produced, the test indicates that the enzyme is doing its job. The rate at which the modified precursor is produced can be compared to a standard to measure the enzyme's efficiency.

Treatment

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. However, treatment options vary depending on the type of porphyria that has been diagnosed. Given the rarity of ALA dehydratase porphyria (six reported cases), definitive treatment guidelines have not been developed.

Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria

Treatment for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria follows the same basic regime. A patient diagnosed with one of these porphyrias can prevent most attacks by avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition, particularly in respect to carbohydrates. In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously.

When an attack occurs, medical attention is needed. Pain is usually severe, and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety; and chloral hydrate or diazepam is useful for sedation or to induce sleep. Intravenously administered hematin may be used to curtail an attack. This drug seems to work by signaling the heme biosynthesis pathway to slow production of precursors. Women, who tend to develop symptoms more frequently than men in response to hormonal fluctuations, may find hormone therapy that inhibits ovulation to be helpful.

Congenital erythropoietic porphyria

The key points of congenital erythropoietic porphyria treatment are avoiding exposure to sunlight and preventing trauma to and infections of the skin. Liberal use of sunscreens and taking beta-carotene supplements can provide some protection from sun-induced damage. Medical treatments such as removing the spleen or administering red blood cell transfusions can have short-term benefits, but do not offer a cure. Oral doses of activated charcoal may offer the potential of remission.

Porphyria cutanea tarda

As with other porphyrias, the first line of defense is the avoidance of precipitating factors, especially alcohol. Regular blood withdrawal is a proven therapy for pushing symptoms into remission. For patients who are anemic or cannot have blood drawn for other reasons, chloroquine therapy may be used.

Erythropoietic protoporphyria

Avoiding sunlight, using sunscreens, and taking beta-carotene supplements are typical treatment options for erythropoietic protoporphyria. The drug cholestyramine may reduce the skin's sensitivity to sunlight as well as the accumulated heme precursors in the liver. Liver transplantation has been used in cases of liver failure, but it has not effected a long-term cure of the porphyria.

KEY TERMS

Autosomal dominant— An inheritance pattern in which a trait is determined by one gene in a pair (genes are inherited in pairs; one copy from each parent).

Autosomal recessive— An inheritance pattern in which a trait is expressed only if both genes in a pair code for that particular characteristic (genes are inherited in pairs; one copy from each parent).

Enzyme— A protein molecule that catalyzes a chemical reaction.

Erythropoiesis— The process through which new red blood cells are created; it begins in the bone marrow.

Erythropoietic— Referring to the creation of new red blood cells.

Gene— A portion of DNA (deoxyribonucleic acid) that codes for a specific product, such as an enzyme.

Hematin— A drug that is administered intravenously to halt an acute porphyria attack. It inhibits heme biosynthesis, preventing the further accumulation of heme precursors.

Heme— A large complex molecule contained in hemoglobin and a number of important enzymes throughout the body. Through these factors, it plays a vital role in metabolism and oxygen and energy transport. Heme is composed of porphyrin and an iron atom.

Hemoglobin— A molecule composed of heme and protein that enables red blood cells to transport oxygen throughout the body. Hemoglobin gives red blood cells their characteristic color.

Hepatic— Referring to the liver.

Neuropathy— A condition characterized by nerve damage. Major symptoms can include weakness, numbness, paralysis, or pain in the affected area.

Porphyrin— A large molecule shaped somewhat like a four-leaf clover. Combined with an iron atom, it forms a heme molecule.

Protoporphyrin— A precursor molecule to the porphyrin molecule.

Prognosis

Even in the presence of a genetic inheritance for a porphyria, symptom development depends on a variety of factors. In the majority of cases, an individual remains asymptomatic throughout life. Porphyria symptoms are rarely fatal with proper medical treatment, but they may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, it is not as great a danger as was once thought.

Health care team roles

Patients diagnosed with porphyrias are cared for by an interdisciplinary treatment team that may include primary care physicians, hematologists, and dermatologists. Laboratory technologists are involved during the diagnostic process, and nurses, health educators, and genetic counselors provide instruction about how to recognize triggers and prevent attacks or flares of the condition.

Prevention

For the most part, the porphyrias are attributable to inherited genes; such an inheritance cannot be prevented. However, symptoms can be prevented or limited by avoiding factors that trigger development.

When there is a family history of porphyria, individuals should consider testing to determine whether they carry the associated gene. Even if symptoms are absent, it is useful to know about the presence of the gene to assess the risks of developing the associated porphyria. This knowledge also reveals whether the individual's offspring may be at risk. Theoretically, it is possible to perform prenatal tests. However, these tests would not indicate whether the child would develop porphyria symptoms; only that they might have the genetic predisposition to develop symptoms.

Resources

PERIODICALS

Fodinger, M. and Sunder-Plassman, G. "Inherited Disorders of Iron Metabolism." Kidney International Supplement 55, no. 69 (March 1999): S22-S34.

Murphy, G.M. "The Cutaneous Porphyrias: A Review." British Journal of Dermatology 140, no. 4 (April 1999): 573-581.

Nordmann, Y. et al. "The Porphyrias." Journal of Hepatology Supplement 30, no. 1 (1999): 12-16.

ORGANIZATIONS

American Porphyria Foundation. P.O. Box 22712, Houston, TX 77227. (713) 266-9617. 〈http://www.enterprise.net/apf/〉.