What is porphyria

Porphyria is the umbrella term for a group of rare disorders caused by abnormalities in the chemical steps that lead to ‘heme’ or ‘haem’ production. Heme (haem) is a vital molecule for all of your body’s organs, although it is most abundant in the blood, bone marrow, and liver. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Normally, your body makes heme in a multi-step process (see Figure 2 below). Porphyrins are made during several steps of this process. People with porphyria are lacking certain enzymes needed for this process. This causes abnormal amounts of porphyrins or related chemicals to build up in the body. Porphyria occurs when the body cannot convert naturally occurring compounds (called ‘porphyrins’) into heme. Porphyrins are substances that are required for the production of red blood cells. A common feature in all porphyrias is the accumulation in the body of porphyrins or porphyrin precursors. Although these are normal body chemicals, they normally do not accumulate. Precisely which of these chemicals builds up depends on the type of porphyria.

Researchers have identified at least 8 types of porphyria that are all caused by a build up of porphyrins in the cells of the body, which are distinguished by their genetic cause and their signs and symptoms. People who have porphyria can experience a wide range of symptoms depending on the type of porphyria they have. There are 2 main types of porphyrias. One affects the skin (cutaneous porphyrias) and the other affects the nervous system (acute porphyrias). Some types of porphyria, called cutaneous porphyrias, primarily affect the skin. Areas of skin exposed to the sun become fragile and blistered, which can lead to infection, scarring, changes in skin coloring (pigmentation), and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, and porphyria cutanea tarda.

Symptoms of cutaneous porphyrias include:

• oversensitivity to sunlight
• blisters on exposed areas of the skin
• itching and swelling on exposed areas of the skin

The nervous system type is called acute porphyria. Symptoms include pain in the chest, abdomen, limbs, or back; muscle numbness, tingling, paralysis, or cramping; vomiting; constipation; and personality changes or mental disorders. These symptoms come and go. Acute porphyrias are described as “acute” because their signs and symptoms appear quickly and usually last a short time. Episodes of acute porphyria can cause abdominal pain, vomiting, constipation, and diarrhea. During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations. These signs and symptoms can be life-threatening, especially if the muscles that control breathing become paralyzed. Acute porphyrias include acute intermittent porphyria and ALA dehydratase deficiency porphyria. Two other forms of porphyria, hereditary coproporphyria and variegate porphyria, can have both acute and cutaneous symptoms.

Certain triggers can cause an attack, including some medicines, smoking, drinking alcohol, infections, stress, and sun exposure. Attacks develop over hours or days. They can last for days or weeks.

Symptoms of acute porphyrias include:

• pain in the abdomen—the area between the chest and hips
• pain in the chest, limbs, or back
• nausea and vomiting
• constipation—a condition in which an adult has fewer than three bowel movements a week or a child has fewer than two bowel movements a week,
• depending on the person
• urinary retention—the inability to empty the bladder completely
• confusion
• hallucinations
• seizures and muscle weakness

Symptoms of acute porphyrias can develop over hours or days and last for days or weeks. These symptoms can come and go over time, while symptoms of cutaneous porphyrias tend to be more continuous. Porphyria symptoms can vary widely in severity.

The porphyrias are rare diseases. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the prevalence of the most common porphyria, porphyria cutanea tarda, is 1 in 10,000, the most common acute porphyria, acute intermittent porphyria, is about 1 in 20,000, and the most common erythropoietic porphyria, erythropoietic protoporphyria, is estimated at 1 in 50,000 to 75,000. Congenital erythropoietic porphyria is extremely rare with prevalence estimates of 1 in 1,000,000 or less. Only 6 cases of ALA dehydratase-deficiency porphyria are documented.

The porphyrias can also be split into erythropoietic and hepatic types, depending on where damaging compounds called porphyrins and porphyrin precursors first build up in the body. In erythropoietic porphyrias, these compounds originate in the bone marrow. Erythropoietic porphyrias include erythropoietic protoporphyria and congenital erythropoietic porphyria. Health problems associated with erythropoietic porphyrias include a low number of red blood cells (anemia) and enlargement of the spleen (splenomegaly). The other types of porphyrias are considered hepatic porphyrias. In these disorders, porphyrins and porphyrin precursors originate primarily in the liver, leading to abnormal liver function and an increased risk of developing liver cancer.

Figure 1. Porphyrin

Figure 2. Heme synthesis

Figure 3. Heme (haem) – oxygenation of heme protein

Environmental factors can strongly influence the occurrence and severity of signs and symptoms of porphyria. Alcohol, smoking, certain drugs, hormones, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of some forms of the disorder. Additionally, exposure to sunlight worsens the skin damage in people with cutaneous porphyrias.

In most cases, the cause is a combination of genetic and environmental factors. More women than men are affected for reasons unknown. There is no cure but treatments are available to manage the symptoms.

Porphyria can be hard to diagnose. It requires blood, urine, and stool tests. Each type of porphyria is treated differently. Treatment may involve avoiding triggers, receiving heme through a vein, taking medicines to relieve symptoms, or having blood drawn to reduce iron in the body. People who have severe attacks may need to be hospitalized.

Porphyria common triggers

Various triggers can prompt the development of porphyria. While the factors in the following list may seem to have nothing in common, each one demands increased heme production, which overwhelms the body’s ability to deal with the increased levels of porphyrins.

Common triggers include:

• Prescription drugs such as barbiturates, tranquilizers, sedatives, oral contraceptives and some types of antibiotics
• Female sex hormones
• Sunlight
• Alcohol
• Cigarette smoking
• Infection
• Surgery
• Fasting.

Porphyria types

There are at least eight types of porphyria, with the two most common being:

• Cutaneous porphyrias, mainly affecting skin with painful blistering upon exposure to sunlight (photosensitivity):
  • The cutaneous porphyrias are sub-categorized as:
    • Porphyria cutanea tarda
    • Erythropoietic protoporphyria
    • Congenital erythropoietic porphyria
    • X-Linked Protoporphyria
• Acute porphyrias, mainly affecting the neurological system characterized by intense pain, confusion and limb weakness:
  • The acute porphyrias are sub-categorized as:
    • Acute intermittent porphyria
    • Hereditary coproporphyria
    • Variegate porphyria
    • ALA dehydratase deficiency porphyria

Porphyria is usually inherited, but it can also occur without anyone else in the family having it.

Experts also classify porphyrias as erythropoietic or hepatic:

• In erythropoietic porphyrias, the body overproduces porphyrins, mainly in the bone marrow.
• In hepatic porphyrias, the body overproduces porphyrins and porphyrin precursors, mainly in the liver.

Table 1 lists each type of porphyria, the deficient enzyme responsible for the disorder, and the main location of porphyrin buildup.

Table 1. Types of porphyria

Porphyria Cutanea Tarda

This disease is the most common of the porphyrias and results from a deficiency of the enzyme uroporphyrinogen decarboxylase. Porphyria cutanea tarda is essentially an acquired disease, but some individuals have a genetic (autosomal dominant) deficiency of enzyme uroporphyrinogen decarboxylase that contributes to development of porphyria cutanea tarda.

• Porphyria cutanea tarda type 1 (Sporadic porphyria cutanea tarda): In approximately 75% to 80% of cases this enzyme uroporphyrinogen decarboxylase deficiency is acquired;
• Porphyria cutanea tarda type 2 (Familial porphyria cutanea tarda): In the remaining cases (20% to 25%), individuals have a genetic predisposition to developing the disorder, specifically a mutation in the uroporphyrinogen decarboxylase gene. Most individuals with this genetic mutation do not develop porphyria cutanea tarda; the mutation is a predisposing factor and additional factors are required for the development of the disorder in these individuals. These factors are called susceptibility factors and are required for the development of both sporadic and familial porphyria cutanea tarda.

Generally, porphyria cutanea tarda develops in mid to late adulthood. In extremely rare cases, individuals have mutations in both uroporphyrinogen decarboxylase genes. This autosomal recessive form of familial porphyria cutanea tarda is known as hepatoerythropoietic porphyria. Hepatoerythropoietic porphyria occurs in childhood and is usually more severe than porphyria cutanea tarda types 1 or 2. These individuals are referred to as having “familial porphyria cutanea tarda”. Most individuals with the inherited enzyme deficiency remain latent and never have symptoms.

Porphyria cutanea tarda is one of the hepatic porphyrias. Large amounts of porphyrins build up in the liver when the disease is becoming active. The disease becomes active when acquired factors, such as iron, alcohol, Hepatitis C Virus (HCV), HIV, estrogens (used, for example, in oral contraceptives and prostate cancer treatment) and possibly smoking, combine to cause a deficiency of enzyme uroporphyrinogen decarboxylase in the liver. Hemochromatosis, an iron overload disorder, also can predispose individuals to porphyria cutanea tarda.

Porphyria cutanea tarda is a rare disorder that affects males and females. The disorder usually develops after the age of 30 and its onset in childhood is rare. porphyria cutanea tarda is found worldwide and in individuals of all races. The prevalence is estimated to be approximately 1 in 10,000 to 25,000 individuals in the general population. porphyria cutanea tarda is the most common form of porphyria.

Figure 4. Porphyria cutanea tarda

Porphyria cutanea tarda causes

Porphyria cutanea tarda is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of the disorder. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase within the liver. When uroporphyrinogen decarboxylase levels in the liver decrease to approximately 20% of normal levels, the symptoms of porphyria cutanea tarda may develop.

The uroporphyrinogen decarboxylase enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional uroporphyrinogen decarboxylase result in the abnormal accumulation of specific porphyrins in body, especially within the blood, liver and skin. The symptoms of porphyria cutanea tarda occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with porphyria cutanea tarda. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver.

The exact, underlying mechanisms that cause porphyria cutanea tarda are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals. Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the uroporphyrinogen decarboxylase enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of porphyria cutanea tarda.

The relationship between iron levels and porphyria cutanea tarda has long been established and porphyria cutanea tarda is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and porphyria cutanea tarda is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in porphyria cutanea tarda (e.g. some individuals with symptomatic porphyria cutanea tarda have normal iron levels).

There is an increased prevalence of mutations in the HFE gene in individuals with porphyria cutanea tarda. Mutations in the HFE gene can cause hemochromatosis, a disorder characterized by the accumulation of iron in the body, especially the liver. Hemochromatosis occurs when a person inherited two mutated HFE genes (one from each parent). Hemochromatosis is associated with low levels of hepcidin, a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract and liver.

Additional risk factors that have been associated with porphyria cutanea tarda include alcohol, certain infections such as hepatitis C or HIV, and drugs such as estrogens. Some studies have indicated that smoking is a risk factor for porphyria cutanea tarda in susceptible individuals. Less often, certain chemical exposures (e.g. hexachlorobenzene), kidney dialysis, and lupus appear to be connected to the development of porphyria cutanea tarda. It is believed that these susceptibility factors reduce hepcidin in the body and consequently lead to iron accumulation in the liver. However, the exact relationship among most susceptibility factors with the development of symptoms in porphyria cutanea tarda is not fully understood. For example, alcohol clearly contributes to the development of the disorder in some cases, but porphyria cutanea tarda is not common in alcoholics. Most individuals with porphyria cutanea tarda have three or more susceptibility factors present.

In some cases, individuals develop porphyria cutanea tarda without a known susceptibility factor, suggesting that additional, as yet unidentified risk factors exist.

The underlying cause of uroporphyrinogen decarboxylase deficiency in the acquired form of porphyria cutanea tarda is unknown. Affected individuals have approximately 50% residual uroporphyrinogen decarboxylase activity and do not develop symptoms unless additional factors are present. The most common factors associated with acquired porphyria cutanea tarda are hemochromatosis or chronic hepatitis C infection. In individuals with acquired porphyria cutanea tarda, uroporphyrinogen decarboxylase levels are only deficient in the liver.

In the familial form of porphyria cutanea tarda, individuals have a mutation in the uroporphyrinogen decarboxylase gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new (de novo) mutation in the affected individual with no family history. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

The uroporphyrinogen decarboxylase gene creates (encodes) the uroporphyrinogen decarboxylase enzyme, which is the fifth enzyme in the heme synthesis pathway. A mutation in one of these genes leads to abnormally low levels of this enzyme in all tissues of the body (not just the liver). However, one mutation alone is insufficient to cause familial porphyria cutanea tarda as residual uroporphyrinogen decarboxylase enzyme levels remain above 20% of normal. In fact, most individuals with a mutation in the uroporphyrinogen decarboxylase gene do not develop the disorder. Additional factors must be present for the disorder to develop.

Porphyria cutanea tarda symptoms

The symptoms of porphyria cutanea tarda can vary greatly from one individual to another. The symptoms of porphyria cutanea tarda are confined mostly to the skin. Blisters develop on sun-exposed areas of the skin (photosensitivity), such as the hands and face. The skin in these areas may blister or peel after minor trauma. Eventually, scarring may develop and affected skin may darken (hyperpigmentation) or fade (hypopigmentation) in color. Abnormal, excessive hair growth (hypertrichosis), especially on the face may also occur. The hair may be very fine or coarse and can differ in color. In some patients, their hair may grow, thicken and darken. Small bumps with a distinct white head (milia) may also develop, especially on the backs of the hands. In some cases, the skin in affected areas may thickened and harden, resembling a condition known as sclerosis, this is sometimes known as pseudosclerosis. Pseudosclerosis in individuals with porphyria cutanea tarda appears as scattered, waxy, harden patches or plaques of skin. Neurological and abdominal symptoms are not characteristic of porphyria cutanea tarda.

Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver (hepatic siderosis), the accumulation of fat in the liver (steatosis), inflammation of certain parts of the liver (portal triaditis), and thickening and scarring around the portal vein (periportal fibrosis). Affected individuals may be at a greater risk than the general population of developing scarring of the liver (cirrhosis) or liver cancer known as hepatocellular carcinoma. Advanced liver disease is uncommon, except in older individuals with recurrent disease. In some cases, liver disease is due to an associated condition such as hepatitis C infection.

Porphyria cutanea tarda, Hepatitis C Virus and HIV

Because porphyria cutanea tarda is frequently associated with hepatitis C virus infection, it is worth noting the issues involved in treating a patient with both porphyria cutanea tarda and hepatitis C virus infection.

Infection with hepatitis C virus is much more common than porphyria cutanea tarda, and most people with hepatitis C virus do not have porphyria cutanea tarda. However, at least in some locations, as many as 80 percent of individuals with porphyria cutanea tarda are infected with hepatitis C virus. Therefore, hepatitis C virus needs to be added to the list of factors that can activate porphyria cutanea tarda alongside alcohol, iron and estrogens. Other hepatitis viruses are seldom implicated in porphyria cutanea tarda, and it is not known how hepatitis C virus activates porphyria cutanea tarda.

There are several different viruses that cause hepatitis. A blood test for hepatitis C virus infection has not been available for very long. Hepatitis C virus is most readily transmitted from one person to another by blood products. Although most people who are infected with hepatitis C virus have a history of exposure to blood or needles contaminated with blood, in some cases it is not known how the infection was acquired. Hepatitis C virus (unlike the hepatitis B Virus and HIV) is seldom transmitted by sexual contact. It is also not readily transmitted by casual contact with other people. Therefore, people infected with hepatitis C virus are not hazardous unless they somehow expose others to their blood.

It is recommended that patients with porphyria cutanea tarda be tested for hepatitis C virus infection. This is done by a blood test that detects antibodies to the virus. If hepatitis C virus infection is found, it may not change the treatment of porphyria cutanea tarda (by phlebotomy or low-dose chloroquine). Treatment for porphyria cutanea tarda is highly successful even in patients with hepatitis C virus. Therefore, it is reasonable to treat the porphyria cutanea tarda first and then look into treatment for hepatitis C virus later.

There are reasons not to treat the hepatitis C virus infection before treating the porphyria cutanea tarda. Hepatitis C virus treatment with alpha-interferon and ribavirin is available but is often not effective. Also, liver damage progresses slowly if at all in many people with hepatitis C virus. However, once the porphyria cutanea tarda is in remission it is important to assess the amount of liver damage the virus has already caused and to have follow-up visits to a doctor to monitor the liver. In some cases it may be important to treat hepatitis C virus infection to try and prevent progressive liver damage.

Porphyria cutanea tarda diagnosis

The preferred screening test for porphyria cutanea tarda is a measurement of porphyrins in plasma. This can differentiate porphyria cutanea tarda from Variegate Porphyria. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. The presence of an inherited deficiency of uroporphyrinogen decarboxylase can be demonstrated by measuring the enzyme in red blood cells and is present in about 20% of patients with porphyria cutanea tarda.

Screening tests can help diagnosis porphyria cutanea tarda by measuring the levels of certain porphyrins in blood plasma. This test can differentiate porphyria cutanea tarda from variegate porphyria and erythropoietic protoporphyria. Screening tests can also be performed on the urine or feces. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. Familial porphyria cutanea tarda can be diagnosed by the presence of a reduced amount of the uroporphyrinogen decarboxylase enzyme in red blood cells (erythrocytes). Molecular genetic testing is available for familial porphyria cutanea tarda if the diagnosis has been confirmed in the patient or a family member by urinary porphyrin analysis and/or enzyme assay of uroporphyrinogen decarboxylase activity.

Porphyria cutanea tarda treatment

The treatment of porphyria cutanea tarda is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

Porphyria cutanea tarda is the most treatable of the porphyrias. Treatment seems to be equally effective in familial and non-familial porphyria cutanea tarda. Factors that tend to activate the disease should be removed. The most widely recommended treatment is a schedule of repeated phlebotomies (removal of blood), with the aim of reducing iron in the liver. This actually reduces iron stores throughout the body. Usually, removal of only 5 to 6 pints of blood (one pint every one to two weeks) is sufficient, which indicates that iron stores are not excessively increased in most porphyria cutanea tarda patients. The best guides to response are measurements of serum ferritin and plasma porphyrins. Phlebotomies are stopped when the ferritin falls to -~20ng/ml. Another treatment approach is a regimen of low doses of either chloroquine (125mg twice weekly) or hydroxychloroquine (100mg twice weekly). Usual dosages of these drugs should not be used because they can cause transient but sometimes severe liver damage and worsening of photosensitivity in porphyria cutanea tarda patients.

After treatment for porphyria cutanea tarda, periodic measurement of plasma porphyrins may be advised, especially if a contributing factor such as estrogen exposure is resumed. If a recurrence does occur, it can be detected early and treated promptly. The treatment of porphyria cutanea tarda is almost always successful, and the prognosis is usually excellent.

Erythropoietic protoporphyria (Protoporphyria)

Erythropoietic protoporphyria is characterized by abnormally elevated levels of protoporphyrin IX in erythrocytes (red blood cells) and plasma (the fluid portion of circulating blood), and by sensitivity to visible light that is usually noticed in early childhood and occurs throughout life. Erythropoietic protoporphyria can result either from mutations of the ferrochelatase gene (FECH), or less commonly the delta-aminolevulinic acid synthase-2 gene (ALAS2). When Erythropoietic protoporphyria is due to an ALAS2 mutation it is termed X-linked protoporphyria, because that gene is found on the X chromosome.

Protoporphyrin accumulates first in the bone marrow in erythropoietic protoporphyria, and then in red blood cells, plasma and sometimes the liver. Protoporphyrin is excreted by the liver into the bile, after which it enters the intestine and is excreted in the feces. It is not soluble in water so is not excreted in the urine.

Erythropoietic protoporphyria is the third most common type of porphyria, and the most common in childhood. It causes very painful photosensitivity and can greatly impair quality of life. Delay in diagnosis is greater than with any other type of porphyria.

Swelling, burning, itching, and redness of the skin may appear during or after exposure to sunlight, including sunlight that passes through window glass. This can cause mild to severe burning pain on sun-exposed areas of the skin. Usually, these symptoms subside in 12 to 24 hours and heal without significant scarring. Blistering and scarring are characteristic of other types of cutaneous porphyria but are unusual in Erythropoietic protoporphyria. Skin manifestations generally begin early childhood and are more severe in the summer.

There is an increased risk of gallstones, which contain protoporphyrin. Excess protoporphyrin can also cause liver damage. Less than 5% of Erythropoietic protoporphyria patients’ severe liver damage and a condition caused protoporphyric hepatopathy that sometimes requires liver transplantation.

Erythropoietic protoporphyria signs and symptoms

The most common symptom of erythropoietic protoporphyria is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with pain, itching, and/or burning of the skin occurring after exposure to sunlight and occasionally to fluorescent light. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also exhibit malformations of the nails. The severity and degree of photosensitivity is different from case to case. Photosensitivity is often seen during infancy; however, in some cases, it may not occur until adolescence or adulthood.

In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or inflammation of the gallbladder (cholecystitis). Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation.

Symptoms usually start in childhood but diagnosis is often delayed since blistering is not common and, because the porphyrins are insoluble, they usually escape detection on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells.

Erythropoietic protoporphyria causes

Erythropoietic protoporphyria is a rare disorder inherited as an autosomal dominant genetic trait with poor penetrance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.

The symptoms of erythropoietic protoporphyria develop due to excessive levels of a chemical called protoporphyrin that accumulates in certain tissues of the body (i.e., the plasma, red blood cells, and the liver). Excessive protoporphyrin levels occur as the result of abnormally low levels of the enzyme ferrochelatase (FECH).

There are several different allelic variants of erythropoietic protoporphyria. An allele is any of a series of two or more genes that may occupy the same position (locus) on a specific chromosome. Symptoms of these allelic variants of erythropoietic protoporphyria are predominantly the same; however, one type may be inherited as an autosomal recessive genetic trait.

The gene that is responsible for regulating the production of the enzyme ferrochelatase (FECH) has been located on the long arm of chromosome 18 (18q21.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”.

Some people who have inherited this defective gene may have slightly elevated levels of protoporphyrin in the body but will not exhibit the symptoms of erythropoietic protoporphyria.

Erythropoietic protoporphyria diagnosis

Erythropoietic protoporphyria should be suspected in anyone with non-blistering photosensitivity especially when it is prolonged and beginning in childhood. It is easy to make a diagnosis, or rule it out, once it is suspected.

The diagnosis of erythropoietic protoporphyria is established by finding an abnormally high level of total erythrocyte protoporphyrin, and showing that this increase is mostly free protoporphyrin rather than zinc protoporphyrin. There is considerable confusion about which test to order. Sometimes laboratories have measured only zinc protoporphyrin and reported results incorrectly as “protoporphyrin” or “free erythrocyte protoporphyrin (FEP)”.

Porphyrins are almost always elevated in plasma in erythropoietic protoporphyria, but may be normal in mild cases. Fecal porphyrins may be normal or increased.

An experienced biochemical laboratory can usually distinguish between patients with erythropoietic protoporphyria and X-linked protoporphyria, because the former have much less zinc protoporphyrin in their erythrocytes. This can be explained because in the marrow the enzyme ferrochelatase not only normally makes heme (iron protoporphyrin) from protoporphyrin and iron, but can also make zinc protoporphyrin, especially when excess protoporphyrin is present or iron is deficient. However, this does not replace DNA studies.

Rarely, erythropoietic protoporphyria develops in adults in the presence of a bone marrow disorder such as polycythemia vera, and is due to expansion of a clone of red blood cell precursors in the marrow that is deficient in ferrochelase.

DNA studies are important for confirming the diagnosis of erythropoietic protoporphyria and X-linked protoporphyria and for genetic counseling. This should be completed first in a person known to have the disease, and the information about the mutations in that individual used to guide testing of family members.

When erythropoietic protoporphyria is due to a FECH mutation the inheritance is described as autosomal recessive. It is most common to find that one severe mutation is inherited from one parent and another weak mutation inherited from the other parent. The weak mutation is quite common in normal Caucasians, rare in Blacks and even more common in Japanese and Chinese populations. This mutation is sometime referred to as “hypomorphic” because it results in formation of a less than normal amount of ferrochelatase. But is does not cause Erythropoietic protoporphyria unless it is paired with a severe mutation. The severe mutation is characteristic for an Erythropoietic protoporphyria family and is present in all affected individuals. “Carriers” of the severe mutation are not affected because they do not have the weak mutation. Affected individuals and unaffected carriers can transmit the severe mutation to the next generation. Some of their children will have Erythropoietic protoporphyria if the other parent has a copy of the weak mutation. Rarely, the weak mutation is absent in an Erythropoietic protoporphyria family and two severe mutations are found, with at least one producing some ferrochelatase.

In X-linked protoporphyria, mutations of the ALAS2 gene, which is found on the X chromosome, causes an increase in the production of the enzyme ALAS2 in the bone marrow. Several of these “gain of function” mutations have been described in different X-linked protoporphyria families. In X-linked protoporphyria protoporphyrin production exceeds that needed for heme and hemoglobin formation. Like hemophilia and other X linked genetic diseases, X-linked protoporphyria is more common in men. Women have two X chromosomes and are usually not affected because they have a normal as well as a mutated ALAS2 gene. Men have only one X chromosome and will be affected if they inherit an ALAS2 mutation. Women with an ALAS2 mutation will, on average, pass that mutation to half of their daughters (who will usually be unaffected carriers) and to half of their sons (who will be affected).

Erythropoietic protoporphyria treatment

1. Sunlight protection

Protection from sunlight is the mainstay of management of erythropoietic protoporphyria, and this is necessary throughout life. Disease severity and porphyrin levels in erythrocytes and plasma probably remain high and relatively constant throughout life in Erythropoietic protoporphyria. However, this has been little studied and more longitudinal observations are needed. Life style, employment, travel and recreation require adjustment in order to avoid painful reactions to sunlight and even from exposure to fluorescent lighting. For these reasons Erythropoietic protoporphyria can substantially affect quality of life.

Protective clothing, including broad-brimmed hats, long sleeves, gloves and trousers (rather than shorts), is beneficial. Several manufacturers specialize on clothing made of closely woven fabrics for people with photosensitivity.

2. Other considerations

In an occasional patient, protoporphyrin causes liver problems, so monitoring liver function is important. Erythropoietic protoporphyria patients should also not use any drug or anesthetic which causes cholestasis (slowing down bile flow), and should also avoid alcohol. Women should avoid medications containing estrogen (birth-control pills, hormone replacement therapy), and men should avoid testosterone supplements, as these substances can also have deleterious effects on the liver of a person with Erythropoietic protoporphyria.

Because erythropoietic protoporphyria is a rare condition, most physicians are not knowledgeable about it. A Medic Alert bracelet with instructions to contact a specialist if needed is a worthwhile precaution.

Yearly monitoring. Testing to include erythrocyte total protoporphyrin, plasma porphyrin, complete blood counts, ferritin and liver function tests should be done yearly. Porphyry levels are expected to be stable and liver tests to remain normal. Erythropoietic protoporphyria patients may have evidence of iron deficiency, and an iron supplement may be advisable if the serum ferritin is below about 20 ng/mL.

Vitamin D. Because they avoid sunlight, Erythropoietic protoporphyria patients are likely to be deficient in vitamin D. A vitamin D supplement with calcium is recommended for bone health.

Liver protection. It is important to avoid other causes of liver disease that might promote the development of liver complications from erythropoietic protoporphyria. Patients should avoid alcohol and other substances that might damage the liver, including many herbal preparations, and be vaccinated for hepatitis A and B.

Surgical lights. Strong operating room lights can cause photosensitivity of the skin and even surfaces of internal organs. Flexible membrane filters, such as CL5-200-X from Madico Co., are available to cover surgical lights and offer some protection. This is especially important in erythropoietic protoporphyria patients with liver failure, which causes even greater increases in protoporphyrin levels and photosensitivity.

Drugs. Drugs that are harmful in other porphyrias are not known to make erythropoietic protoporphyria worse, but are best avoided as a precaution. This may include estrogens and other drugs that might reduce bile formation. A short course of a non-steroidal anti-inflammatory drug can provide some pain relief after an episode of photosensitivity, but can cause ulcerations of the digestive track especially with prolonged use.

Laser treatment. According to Dr. Roth, laser treatments for hair removal or eye surgery have not been a problem in erythropoietic protoporphyria people. But the doctor should be made aware of the diagnosis, and that laser output between 400 and 650 nanometers might be harmful. Before hair removal treatment, the doctor may irradiate a small area of the skin to be treated for the length of time it will take to do the hair removal to ascertain if the patient would react within the period of time that a reaction to sunlight would be expected in that patient.

Children with erythropoietic protoporphyria. Avoiding sunlight can be difficult for children with erythropoietic protoporphyria who have less sunlight tolerance than their friends.

X-Linked Protoporphyria

X-linked protoporphyria is an extremely rare genetic disorder characterized by an abnormal sensitivity to the sun (photosensitivity) that can cause severe pain, burning, and itching of sun-exposed skin. Symptoms may occur immediately or shortly after exposure to the sun, including direct exposure or indirect exposure such as sunlight that passes through window glass or that is reflected off water or sand. Redness and swelling of affected areas can also occur. Blistering and severe scarring occur infrequently. Chronic episodes of photosensitivity may lead to changes in the skin of sun-exposed areas. Some individuals eventually develop potentially severe liver disease. X-linked protoporphyria is caused by mutations of the ALAS2 gene and is inherited as an X-linked dominant trait. Males often develop a severe form of the disorder while females may not develop any symptoms (asymptomatic) or can develop a form as severe as that seen in males.

X-linked protoporphyria causes

X-linked protoporphyria is caused by gain-of-function mutations to the ALAS2 gene and is inherited as an X-linked dominant disorder. X-linked dominant disorders are evident in a female with one normal X chromosome and one affected X chromosome.

The ALAS2 gene is located on the short arm (p) of the X chromosome (Xp11.21)*. The gene encodes a protein known as erythroid specific 5-aminolevulinate synthase 2. Mutations of the ALAS2 gene lead to the overproduction of this enzyme, which, in turn, results in elevated levels of a chemical called protoporphyrin. Protoporphyrin abnormally accumulates in certain tissues of the body, especially the blood, liver, and skin. The symptoms of X-linked protoporphyria develop because of this abnormal accumulation of protoporphyrin. For example, when protoporphyrins absorb energy from sunlight, they enter an excited state (photoactivation) and this abnormal activation results in the characteristic damage to the skin. Accumulation of protoporphyrins in the liver causes toxic damage to the liver and may contribute to the formation of gallstones. Protoporphyrin is formed within red blood cells in the bone marrow and then enters the blood plasma, which carries it to the skin where it can be photoactivated by sunlight and cause damage. The liver removes protoporphyrin from the blood plasma and secretes it into the bile.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, “chromosome Xp22.2-22.1” refers to bands 22.2 through 22.1 on the short arm of chromosome X.

X-linked protoporphyria signs and symptoms

Hypersensitivity of the skin to sunlight is the characteristic finding of X-linked protoporphyria. Affected individuals develop pain, itching, and burning of the skin after exposure to sunlight. Sometimes these symptoms are accompanied by swelling and redness (erythema) of the affected areas. Large blisters and severe scarring, which are common to other forms of cutaneous porphyria, usually do not occur in individuals with X-linked protoporphyria. Symptoms may be noticed as quickly as a few minutes after exposure to the sun. Although most symptoms usually subside within 24-48 hours, pain and a red or purple discoloration of the skin may persist for several days after the initial incident. Pain is disproportionately severe in relation to the visible skin lesions. Pain associated with X-linked protoporphyria can be excruciating and is often resistant to pain medications, even narcotics.

Repeated episodes of photosensitivity may eventually causes changes in the skin of affected individuals. Such changes include thickening and hardening of the skin, development of a rough or leathery texture, small facial pock-like pits, and grooving around the lips.

Some individuals with X-linked protoporphyria develop liver disease, which can range from mild liver abnormalities to liver failure. Information on liver disease is limited, but the risk of liver disease is believed to be higher in X-linked protoporphyria than in EPP. Affected individuals may experience back pain and severe abdominal pain especially in the upper right area of the abdomen. In some affected individuals, the flow of bile through the gallbladder and bile ducts may be interrupted (cholestasis) leading to gallstones. These stones can cause obstruction and inflammation of the gallbladder (cholecystitis). Scarring of the liver (cirrhosis) may also develop and some individuals may eventually develop end stage liver failure.

Additional symptoms have been reported in individuals with X-linked protoporphyria including mild anemia (low levels of circulating red blood cells) and iron deficiency.

X-linked protoporphyria diagnosis

A diagnosis of X-linked protoporphyria is based upon identification of characteristic symptoms (e.g., non-blistering photosensitivity), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.

A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from erythropoietic protoporphyria.

Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).

Additional tests may be performed such as blood tests to evaluate anemia and iron stores in the body and vitamin D levels, or an abdominal sonogram to detect and evaluate liver disease potentially associated with X-linked protoporphyria.

X-linked protoporphyria treatment

The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria. Because the disorder is so rare, most treatment information is based on erythropoietic protoporphyria, which is clinically similar to X-linked protoporphyria.

Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients. Certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.

Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.

A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. For more information on this treatment, contact the organizations listed at the end of this report (i.e. American Porphyria Foundation and the erythropoietic protoporphyriaREF). Another drug sometimes used to improve tolerance to sunlight is cysteine.

In some cases, the drug cholestyramine may be given. Cholestyramine absorbs porphyrin. The drug may interrupt the recirculation of protoporphyrin secreted into the bile back into the liver and promote its excretion through the feces. Other drugs that absorb porphyrins such as activated charcoal have also been used to treat affected individuals. These drugs may lead to improvement of liver disease.

Individuals with any form of protoporphyria should avoid substances associated with cholestasis including alcohol and certain drugs such as estrogens. Immunizations for hepatitis A and B are recommended as well.

Investigational Therapies

Plasmapheresis and red blood cell transfusions have been used to treat people with erythropoietic protoporphyria. In individuals with severe liver disease, a liver transplantation may be required. Extreme caution should be used by physicians considering these treatment options for individuals with X-linked protoporphyria (or erythropoietic protoporphyria). Each individual case should be evaluated on its own merits.

Iron supplementation may be considered in individuals with anemia and abnormal iron metabolism. Such therapy requires strict monitoring by physicians. In erythropoietic protoporphyria, iron supplementation has resulted in clinical improvement, but also carries a risk of increased photosensitivity.

Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is being studied as a protective agent against sunlight in individuals with erythropoietic protoporphyria. This drug increases the production of melanin in the skin. Afamelanotide is available to patients in Europe and is under consideration by the United States Food and Drug Administration (2016). The long-term safety and effectiveness of this drug and its role in treating individuals with X-linked protoporphyria remain under investigation.

Congenital erythropoietic porphyria

This disease is extremely rare and is autosomal recessive. It is also known as Gunther’s disease. The deficient enzyme is uroporphyrinogen III cosynthase (or uroporphyrinogen III synthase). Various mutations in the gene for this enzyme have been identified in different families. As is characteristic of the erythropoietic porphyrias, symptoms begin during infancy. Sometimes congenital erythropoietic porphyria is recognized as a cause of anemia in a fetus before birth. In less severe cases symptoms may begin during adult life. Porphyrins are markedly increased in bone marrow, red blood cells, plasma, urine and feces. Porphyrins are also deposited in the teeth and bones.

Congenital erythropoietic porphyria causes

Congenital erythropoietic porphyria is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Mutations in the UROS gene cause congenital erythropoietic porphyria. The symptoms of congenital erythropoietic porphyria develop due to excessive levels of the specific porphyrins that accumulate in tissues of the body as a result of the markedly impaired function of the UROS enzyme.

Congenital erythropoietic porphyria symptoms

Skin photosensitivity may be extreme, and can lead to blistering, severe scarring and increased hair growth. Bacteria may infect the damaged skin. Facial features and fingers may be lost through phototoxic damage as well as infection. Red blood cells have a shortened life-span, and anemia often results. Synthesis of heme and hemoglobin are actually increased to compensate for the shortened red blood cell survival.

Congenital erythropoietic porphyria diagnosis

The diagnosis of congenital erythropoietic porphyria may be suspected when the reddish-colored urine is noted at birth or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a thorough clinical evaluation and specialized laboratory tests. The diagnosis can be made by testing the urine for increased levels of specific porphyrins. Diagnostic confirmation requires the demonstration of the specific UROS enzyme deficiency and/or the lesion(s) in the UROS gene.

Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in congenital erythropoietic porphyria families.

Congenital erythropoietic porphyria treatment

Avoidance of sunlight is essential to prevent the skin lesions in individuals with congenital erythropoietic porphyria. The use of topical sunscreens, protective clothing, long sleeves, hats, gloves, and sunglasses are strongly recommended. Individuals with congenital erythropoietic porphyria will benefit from window tinting or using vinyls or films to cover the windows in their car or house. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.

In addition to protection from sunlight, the anemia should be treated, if present. Chronic transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins. When successful, bone marrow transplantation has cured patients with congenital erythropoietic porphyria, but is accompanied by specific risks of complications and demise. For more information on this treatment, contact the American Porphyria Foundation.

Blood transfusions and perhaps removing the spleen may reduce porphyrin production by the bone marrow. Activated charcoal given by mouth is sometimes effective. Bone marrow transplantation has been very effective in some patients. Stem cell transplantation and gene therapy may also be an option in the future.

Acute intermittent porphyria

Acute intermittent porphyria one of the hereditary hepatic porphyrias with the prevalence of 1 in 20,000 people. Acute intermittent porphyria inheritance is autosomal dominant. The deficient enzyme is porphobilinogen deaminase, also known as hydroxymethylbilane synthase. This enzyme was formerly known as uroporphyrinogen I-synthase, and this term is still used by some clinical laboratories. A deficiency of porphobilinogen deaminase is not sufficient by itself to produce acute intermittent porphyria, and other activating factors must also be present. These include hormones, drugs and dietary changes. Sometimes, activating factors cannot be identified.

Figure 5. Acute intermittent porphyria autosomal dominant inheritance pattern

Acute intermittent porphyria symptoms

Most people who inherit the gene for acute intermittent porphyria never develop symptoms. However, experts recommend that all relatives of someone with acute intermittent porphyria obtain testing, to determine who has the genetic trait and who does not. Those who test positive for the trait should be educated as to measures that will help avoid attacks. Prevention is essential to good management.

Acute intermittent porphyria manifests after puberty, especially in women (due to hormonal influences). Symptoms usually come as discrete attacks that develop over two or more days. Abdominal pain, which is associated with nausea, can be severe and occurs in most cases.

Other symptoms may include:

• nausea
• vomiting
• constipation
• pain in the back, arms and legs
• muscle weakness (due to effects on nerves supplying the muscles)
• urinary retention
• palpitation (due to a rapid heart rate and often accompanied by increased blood pressure)
• confusion, hallucinations and seizures

Sometimes the level of salt (sodium and chloride) in the blood decreases markedly and contributes to some of these symptoms. The skin is not affected.

Acute intermittent porphyria diagnosis

Because this disease is rare and can mimic a host of other more common conditions, its presence is often not suspected. On the other hand, the diagnosis of acute intermittent porphyria and other types of porphyria is sometimes made incorrectly in patients who do not have porphyria at all, particularly if laboratory tests are improperly done or misinterpreted. The finding of increased levels of delta-aminolevulinic acid and porphobilinogen in urine establishes that one of the acute porphyrias is present. If porphobilinogen deaminase is deficient in normal red blood cells, the diagnosis of acute intermittent porphyria is established. However, measuring porphobilinogen deaminase in red blood cells should not be relied upon by itself to exclude acute intermittent porphyria in a sick patient, because the enzyme is not deficient in red blood cells of all acute intermittent porphyria patients.

If it is known that someone in a family has acute intermittent porphyria, and their enzyme value is low in red blood cells, other family members who have inherited a deficiency of porphobilinogen deaminase can be identified by measuring the enzyme in their red blood cells. Latent cases so identified can avoid agents known to cause attacks. However, in some acute intermittent porphyria families, porphobilinogen deaminase is normal in red blood cells and is deficient only in the liver and other tissues. Falsely low values sometimes occur due to problems with collecting and transporting the sample.

DNA is the material in cells that encodes all the genetic information of an individual. Many different mutations have been identified in the portion of DNA that comprises the gene for porphobilinogen deaminase. However, within a given family, everyone has the same mutation. When that mutation is known for one member, screening of the relatives is straightforward and can be done on DNA from saliva (spit) or a swab of the inside of the cheek. This is now the gold standard of diagnosis and is available through specialty labs.

Acute intermittent porphyria treatment

Hospitalization is often necessary for acute attacks, particularly if nausea and vomiting have prevented adequate oral intake. Medications for pain, nausea and vomiting, intravenous (IV) hydration, and close observation are generally required.

Glucose and other carbohydrates can help suppress disease activity, are given by vein or by mouth, and are part of initial treatment. Intravenous heme, however, is both more specific and effective than glucose and should be started if the patient’s symptoms fail to improve within 36 hours. Heme is sold as Panhematin®, from Recordati Rare Diseases (http://www.recordatirarediseases.com/products/). Most hospitals do not stock it. Therefore the pharmacy must be notified at the time the patient’s admission to initiate a request for air-freighting enough medication for 5 days of treatment. Generally, shipping will take at least 24 hours.

Panhematin, is the only commercially available form of heme for treatment and prevention of acute porphyric attacks in the United States. Heme arginate, which is marketed in other countries as Normosang® (Orphan Europe), is another preparation for intravenous administration. The main side-effect of Panhematin® is irritation of the vein used for infusion (phlebitis). This is avoided by slow infusion through a large caliber vein or central line. Adding human albumin to the heme solution also may reduce the risk of phlebitis. (Directions for preparing Panhematin® in this manner can be obtained from porphyria specialist and is included in the Primary Care Physician/Emergency Room Kit.) Heme therapy is indicated only if an acute attack of porphyria is proven by a marked increase in urine porphobilinogen. It may be useful also as preventive therapy for people with frequent recurrent attacks.

During treatment of an attack, attention should be given to salt and water balance. Harmful drugs should be stopped. These include barbiturates, sulfonamides, and many others (see the full list here: http://www.porphyriafoundation.com/drug_database/). Attacks are often precipitated by low intake of carbohydrates and calories in an attempt to lose weight. Thus dietary counseling is very important. Premenstrual attacks often resolve quickly with the onset of menses; hormone manipulations may prevent such attacks.

Acute intermittent porphyria is particularly dangerous if the diagnosis has not been made and if harmful drugs are administered. The prognosis is usually good if the disease is recognized and if treatment and preventive measures are begun before severe nerve damage has occurred. Although symptoms usually resolve after an attack, some patients develop chronic pain. Nerve damage and associated muscle weakness can improve over a period of months or longer after a severe attack. Mental symptoms may occur during attacks, but are usually not chronic.

Wearing a Medic Alert bracelet is advisable for patients who have had attacks. People who are asymptomatic carriers of the genetic trait may choose not to wear a bracelet but should be prepared in any medical encounter to advise their care-givers of medications that are risky in Acute intermittent porphyria. It should be remembered that Acute intermittent porphyria patients can develop other diseases, and symptoms will not always be due to porphyria.

Acute intermittent porphyria diet

Acute intermittent porphyria patients prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intakes of carbohydrate and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician, who may request that a dietitian estimate an individual’s normal caloric intake, which varies greatly from one person to another. It may be appropriate to prescribe a diet that is approximately 10% below the normal level of calories for the patient. This should result in a gradual weight loss and usually will not cause an attack of porphyria.

Acute intermittent porphyria and having children

Pregnancy is tolerated much better than was formerly believed. Offspring have a 50% chance of inheriting the gene for acute intermittent porphyria, but the great majority of them remain “latent” for all or most of their lifetimes. The minority that eventually have symptoms usually benefit from treatment. Given these considerations, most patients or individuals with “latent” porphyria elect to have children for the same reasons as anyone else.

Variegate porphyria

Variegate porphyria is caused by a mutation in the enzyme protoporphyrinogen oxidase, which is part of the pathway that produces porphyrins and heme. Acute attacks are similar to those in Acute intermittent porphyria and hereditary coproporphyria but are unusual. A more common sign of the disease is blistering skin lesions, which are chronic in many people with variegate porphyria.

Acute attacks almost always start with severe pain in the abdomen but sometimes in the chest, back, or thighs, and are often accompanied by nausea, vomiting, and constipation. Heart rate and blood pressure are commonly increased. These symptoms and signs are all due to the effects of the disease on the nervous system. Confusion, convulsions, and muscular weakness, due to impairment of the nerves controlling the muscles, may lead to paralysis. An acute attack usually lasts for days or weeks. Recovery from severe paralysis is generally slow.

Variegate porphyria is especially common in South Africa in individuals of Dutch ancestry, where it has been estimated that 3 in 1,000 of the white population are affected. It is much less prevalent in other countries. Like acute intermittent porphyria and hereditary coproporphyria, it is an autosomal dominant disorder, meaning that a mutation is present in only one of the pair of protoporphyrinogen oxidase genes.

Figure 6. Variegate porphyria autosomal dominant inheritance pattern

Variegate porphyria causes

As in hereditary coproporphyria, acute attacks of variegate porphyria are unusual except in the presence of environmental activating factors, such as drugs, hormones, and dietary changes.

Variegate porphyria is caused by mutations of the protoporphyrinogen oxidase gene. A protoporphyrinogen oxidase mutation is inherited as an autosomal dominant trait within a family. The pattern of inheritance is autosomal dominant, which means that a single mutation is inherited from one parent and, in the presence of other triggering factors, is sufficient to cause the disease. The abnormal gene can be inherited from either parent, or on rare occasions can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

The protoporphyrinogen oxidase gene is located on the long arm (q) of chromosome 1 (1q22). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q22” refers to band 22 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The protoporphyrinogen oxidase gene contains instructions for creating protoporphyrinogen oxidase, one of the eight enzymes necessary for the production of heme. Heme is an iron-containing porphyrin (iron protoporphyrin) and is a part of many heme-containing proteins (hemoproteins) in the body. Hemoproteins interact with oxygen and some are involved in electron transport and energy metabolism. The best known hemoprotein is hemoglobin, which is made in the bone marrow, makes red blood cells red, and transports oxygen from the lungs to other tissues. However, the bone marrow and hemoglobin are not affected in variegate porphyria. In this condition the heme pathway in the liver, which makes heme for other important hemoproteins, is affected.

Mutations of the protoporphyrinogen oxidase gene result in deficient levels of protoporphyrinogen oxidase, which, in turn, disrupts the biochemical process to create heme in the liver. This disruption causes porphyrins and porphyrin precursors to accumulate in the liver and these are then transported to other parts of the body to affect the nervous system and skin.

A variety of different triggers are known to lead to attacks in individuals with variegate porphyria. Many of these triggers act by increasing heme synthesis in the liver, which makes the protoporphyrinogen oxidase deficiency more significant and increases the accumulation of porphyrins and porphyrin precursors. As noted above, triggers include a variety of drugs, hormones (especially progesterone), reduced intake of calories and carbohydrate, alcohol, and stress induced by infection or other illness.

Variegate porphyria diagnosis

Urine aminolevulinic acid and porphobilinogen are increased during attacks, but as in hereditary coproporphyria, these may increase less and decrease more rapidly than in acute intermittent porphyria. Plasma porphyrins are frequently increased in variegate porphyria, in contrast to acute intermittent porphyria and hereditary coproporphyria, and the plasma of variegate porphyria patients displays a distinctive fluorescence peak, which is diagnostic. Fecal porphyrins are also elevated and are predominantly coproporphyrin III and protoporphyrin.

Molecular genetic testing to identify a protoporphyrinogen oxidase mutation is recommended for all biochemically confirmed cases of variegate porphyria. Molecular testing is sometimes useful when symptoms have been absent for months or years and biochemical abnormalities are no longer present. Knowing the protoporphyrinogen oxidase mutation is a family enables other family members to be tested reliably for the same mutation.

Variegate porphyria treatments

Management and prevention are the same as in acute intermittent porphyria and hereditary coproporphyria. Hospitalization is usually indicated for pain control and treatment of other severe symptoms such as nausea and vomiting, electrolyte imbalances and convulsions. Monitoring for these manifestations as well and muscle weakness and respiratory embarrassment is also indicated in severe attacks. A narcotic analgesic is generally required for pain, and a phenothiazine or ondansetron for nausea and vomiting. Triggering factors should be identified and discontinued when possible. Specific therapies are hemin for injection, which is available in the U.S. as lyophilized hematin (Panhematin®,), and glucose loading. Hemin represses the heme pathway in the liver and lowers aminolevulinic acid, porphobilinogen and porphyrins, and is associated with more rapid recovery from an attack. Glucose given intravenously has a similar effect, but because it is less potent is used only for mild attacks, or until hemin can be obtained from the manufacturer. Blistering skin lesions are much more common than in hereditary coproporphyria and are not readily treated. The only effective preventive measure is use of protective clothing.

Variegate porphyria prognosis

The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops. Although symptoms usually resolve after an attack, recovery of neuromuscular function (in a severe case) may require several months. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

Can attacks be prevented?

Yes, particularly with regard to drugs and diet. Genetic Variegate Porphyria carriers should become informed on medications to avoid and should be prepared to point their healthcare providers to on-line drug lists that are regularly updated.

A Medic Alert bracelet is useful for a situation in which the patient is incapacitated. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue (Lupron, Zoladex, others) administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.

Individuals who are prone to attacks should consume a normal balanced diet. Despite on-line discussion, there is no evidence that pushing carbohydrate prevents attacks, and it has the side effect of weight gain, which is undesirable for most people. Fasting, fad diets (for example, high protein) and gastric reduction surgery should be avoided. If weight loss is desired, it is advisable to consult a physician and a dietitian about an individualized diet with modest caloric restriction (ca. 10%), which will produce gradual weight loss without increasing the risk of an attack of porphyria. Exercise is safe in porphyria, and recommended.

Hereditary coproporphyria

Hereditary coproporphyria is due to a mutation in coproporphyinogen oxidase, which is part of the pathway that produces porphyrins and heme. It is an autosomal dominant disorder, meaning that a mutation is present in only one of the pair of coproporphyinogen oxidase genes. The incidence of active hereditary coproporphyria appears to be at most 2 per 1,000,000. The prevalence of the genetic carrier state is unknown.

Hereditary coproporphyria is termed a disease with low penetrance, meaning that many genetic carriers (defined by having a coproporphyinogen oxidase mutation) never have signs or symptoms of active porphyria. Active disease in general requires the presence of environmental factors such as certain drugs, hormones, and dietary changes, as in acute intermittent porphyria. Lists are available of drugs that are risky for hereditary coproporphyria genetic carriers as well as drugs that are safe (see the full list here: http://www.porphyriafoundation.com/drug_database/). The worst offenders are barbiturates, sulfonamide antibiotics, anti-seizure drugs, rifampin, and oral contraceptives (progesterone, in particular). Attacks in women may occur after ovulation and during the last part of the menstrual cycle when progesterone levels are high. Reduced food intake, often in an effort to lose weight, as well as infections, surgery, and stressful situations may also precipitate attacks. Alcohol has been implicated in some attacks. People with repeated attacks are at risk for developing chronic renal disease and liver cancer (hepatocellular carcinoma)

Hereditary coproporphyria diagnosis

The initial test for people with symptoms is quantitative urinary aminolevulinic acid, porphobilinogen and porphyrins. Elevation of aminolevulinic acid, porphobilinogen and coproporphyrin (predominantly isomer III) is highly suggestive of Hereditary coproporphyria. For asymptomatic individuals, the urine studies may be normal, but a fecal porphyrin analysis will show elevation of coproporphyrin III. Screening tests of this kind should be confirmed by DNA analysis to confirm a coproporphyinogen oxidase mutation.

Hereditary coproporphyria treatment

Treatment, complications, and preventive measures are the same as in acute intermittent porphyria. Hospitalization is often necessary for acute attacks. Medications for pain, nausea, and vomiting and close observation are generally required. During treatment of an attack, attention should be given to sodium (salt) and water balance. Harmful drugs should be stopped. Attacks are treated with either glucose loading or hemin (Panhematin®, Recordati). These are specific treatments that lower the production of heme pathway intermediates by the liver. Glucose or other carbohydrates are given by mouth if possible, otherwise by vein. However, unless an attack is mild, it is now common practice to give hemin as soon as it is available, because it works more quickly than glucose loading, preventing the neurological complications of prolonged attacks.

Patients with severe renal disease tolerate hemodialysis or kidney transplantation. Liver transplantation has been very effective for patients who have repeated attacks and who are resistant to other treatments. However, experience with transplantation as a treatment is still limited.

Hereditary coproporphyria prognosis

The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops. Although symptoms usually resolve after an attack, recovery of neuromuscular function (in a severe case) may require several months or longer. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

Can attacks be prevented?

Yes, particularly with regard to drugs and diet. Genetic hereditary coproporphyria carriers should become informed on drugs and other factors that can lead to symptoms (see above). They should be prepared to point their healthcare providers to drugs and medications to avoid. A Medic Alert bracelet is useful for a situation in which the patient is incapacitated. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.

Individuals who are prone to attacks should consume a normal balanced diet. Despite online discussion, there is no evidence that pushing carbohydrate prevents attacks, and it has the side effect of weight gain, which is undesirable for most people. Fasting, fad diets (for example, high protein) and gastric reduction surgery should be avoided. If weight loss is desired, it is advisable to consult a physician and a dietitian about an individualized diet with modest caloric restriction, which will produce gradual weight loss without increasing the risk of an attack of porphyria. Exercise is safe in porphyria, and recommended.

ALA dehydratase deficiency porphyria

ALA dehydratase deficiency porphyria is a severe disorder caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase which results in an increase of 5’-aminolevulinic acid (ALA) in the liver, other tissues, blood plasma, and urine. In addition, urine coproporphyrin and erythrocyte protoporphyrin are increased. ALA dehydratase deficiency porphyria generally presents with sudden attacks of severe stomach pain that last for several days.

All of the reported cases of ALA dehydratase deficiency porphyria have been males, in contrast to the other acute porphyrias. ALA dehydratase deficiency porphyria is the least common of all the porphyrias with less than 10 cases documented to date. This is an autosomal recessive disease, whereas the other three acute porphyrias are autosomal dominant. Each parent of an affected individual must have a mutation in one of their δ-aminolevulinic acid dehydratase genes and both must pass their mutation on to their child.

ALA-dehydratase porphyria causes

ALA dehydratase deficiency porphyria is caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase (ALAD).

ALA dehydratase deficiency porphyria is caused by mutations in the ALA dehydratase deficiency gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALA dehydratase deficiency gene have a mutation. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

The ALA dehydratase deficiency gene contains instructions for creating the enzyme aminolevulinate dehydratase, which is necessary for the production of heme. Heme is part of hemoglobin, which is the oxygen-carrying component of red blood cells. Heme is mainly produced in the bone marrow and the liver. Eight different enzymes are necessary for the creation of heme.

Mutations of the ALA dehydratase deficiency gene result in deficient levels ofporphobilinogen in the body, with accumulation of ALA, which causes the symptoms associated with ALA dehydratase deficiency porphyria.

A variety of different triggers have been identified that can precipitatean acute attack in individuals with ALA dehydratase deficiency porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspect of triggering an acute attack.

ALA dehydratase deficiency porphyria diagnosis

There are many laboratory tests available for the porphyrias, and it is often difficult to decide which should be chosen. Many of these tests are expensive and the results are often difficult to interpret. When abdominal and neurological symptoms suggest an acute porphyria, the best screening tests are urinary aminolevulinic acid (ALA) and porphobilinogen (PBG). DNA testing to identify the specific mutation in an individual’s porphyria-causing gene is the most specific and sensitive test to confirm the diagnosis of a specific porphyria. Before requesting DNA testing, it is recommended that patients have biochemical testing (urinary, stool and/or plasma porphyrins and porphyrin precursors (ALA and PBG) and/or enzyme assays). However, biochemical testing may be inconclusive.

ALA dehydratase deficiency porphyria treatment

Treatment is the same as in the other acute porphyrias. For the acute porphyrias, hospitalization is often necessary for acute attacks. Medications for pain, nausea and vomiting, and close observation are generally required with monitoring of salt and water balance. Harmful drugs should be stopped. Attacks are treated with either glucose loading or intravenous administration of hemin (Panhematin®). Attacks can be prevented in many cases by avoiding harmful drugs and adverse dietary practices.

Porphyria complications

Possible complications depend on the form of porphyria:

• Acute porphyrias can be life-threatening if an attack isn’t promptly treated. During an attack, you may experience dehydration, breathing problems, seizures and high blood pressure. Episodes often require hospitalization for treatment. Long-term complications with recurrent acute attacks may include chronic pain, chronic kidney failure and liver damage.
• Cutaneous porphyrias can result in permanent skin damage. Also, the skin blisters can become infected. When your skin heals after cutaneous porphyria, it may have an abnormal appearance and coloring, be fragile, or leave scars.

Without medical treatment, complications of porphyria may include:

• Permanent hair loss
• Skin scarring
• Permanent skin pigmentation changes
• Dehydration
• Breathing problems
• High blood pressure (hypertension)
• Low salt levels in the blood (hyponatremia)
• Kidney failure
• Liver problems, which may require a liver transplant in severe cases.

Porphyria causes

The substance heme (or haem) is used in various metabolic processes. The body makes heme from porphyrins, which are metallic compounds found naturally in the tissues of animals and plants. The conversion of porphyrins into heme requires the action of special proteins called enzymes. Genes control the action of enzymes. A flawed gene (or genes) can stop the body from making one or more of these enzymes. This creates a lack of heme and a build-up of porphyrins, which causes the signs and symptoms of porphyria.

Genetic forms

Most forms of porphyria are inherited, which means the genetic predisposition is passed from one generation to the next. The faulty gene interferes with the body’s ability to create one or more enzymes necessary in the conversion of porphyrins into heme. The pattern of inheritance may include:

• Autosomal dominant inheritance – the faulty gene is inherited from one parent. This faulty gene overrides the healthy gene inherited from the other parent.
• Autosomal recessive inheritance – the faulty gene is inherited from both parents.

However, about nine in every 10 people with the faulty gene or genes don’t have porphyria. It appears that an environmental trigger is needed to allow porphyria to develop. You might have what’s called latent porphyria, and never have symptoms. This is the case for most carriers of the abnormal genes.

Acquired forms

Porphyria cutanea tarda typically is acquired rather than inherited, although the enzyme deficiency may be inherited. Certain triggers that impact enzyme production — such as too much iron in the body, liver disease, estrogen medication, smoking or excessive alcohol use — can cause symptoms.

Porphyria cutanea tarda is usually an acquired disorder, meaning factors other than genes cause the enzyme deficiency. This type of porphyria can be triggered by

• too much iron
• use of alcohol or estrogen
• smoking
• chronic hepatitis C—a long-lasting liver disease that causes inflammation, or swelling, of the liver
• HIV—the virus that causes AIDS
• abnormal genes associated with hemochromatosis—the most common form of iron overload disease, which causes the body to absorb too much iron

Risk factors for porphyria

In addition to genetic risks, environmental factors may trigger the development of signs and symptoms in porphyria. When exposed to the trigger, your body’s demand for heme production increases. This overwhelms the deficient enzyme, setting in motion a process that causes a buildup of porphyrins.

Examples of triggers include:

• Exposure to sunlight
• Certain medications, including hormone drugs
• Recreational drugs
• Dieting or fasting
• Smoking
• Physical stress, such as infections or other illnesses
• Emotional stress
• Alcohol use
• Menstrual hormones ― acute porphyria attacks are rare before puberty and after menopause in women.

Porphyria symptoms

The signs and symptoms of porphyria can vary, depending on the type and severity. Some people have no symptoms. Some go for long periods without any symptoms. Some people have quite a bit of trouble with symptoms.

The most common symptoms are:

• skin problems like sensitivity to the sun, blistering, discoloration and scarring
• abdominal pain
• muscle weakness
• numbness in the arms and legs
• confusion and seizures.

Symptoms vary from one type of porphyria to the next. Cases are generally classified into one of three groups, which include:

• Acute porphyrias – the condition mostly affects the nervous system. The skin is occasionally affected. Symptoms may include muscle pain or paralysis, seizures, disorientation, hallucination, bloody (red) urine, hypertension and gastrointestinal problems such as vomiting, abdominal pain and constipation. Acute porphyrias generally occur during adulthood and are rare before puberty or after menopause. Different types of acute porphyria include ‘acute intermittent porphyria’ and ‘erythropoietic protoporphyria’.
  • Signs and symptoms of acute porphyria may include:
    • Severe abdominal pain
    • Pain in your chest, legs or back
    • Constipation or diarrhea
    • Nausea and vomiting
    • Muscle pain, tingling, numbness, weakness or paralysis
    • Red or brown urine
    • Mental changes, such as anxiety, confusion, hallucinations, disorientation or paranoia
    • Breathing problems
    • Urination problems
    • Rapid or irregular heartbeats you can feel (palpitations)
    • High blood pressure
    • Seizures
• Cutaneous porphyrias – the condition affects the skin but not the nervous system. The skin is highly sensitive to sunlight and exposure tends to trigger symptoms within minutes. Symptoms may include red, itchy, blistered, painful and swollen skin and bloody (red) urine. The condition may develop during childhood. Different types of cutaneous porphyria include ‘porphyria cutanea tarda’ and ‘hepatoerythropoietic porphyria’.
  • As a result of sun exposure, you may experience:
    • Sensitivity to the sun and sometimes artificial light, causing burning pain
    • Sudden painful skin redness (erythema) and swelling (edema
    • Blisters on exposed skin, usually the hands, arms and face
    • Fragile thin skin with changes in skin color (pigment)
    • Itching
    • Excessive hair growth in affected areas
    • Red or brown urine
• Neurocutaneous porphyrias – the condition affects both the skin and the nervous system. Sunlight exposure tends to rapidly trigger symptoms. Different types of neurocutaneous porphyria include ‘variegate porphyria’ and ‘hereditary coproporphyria’.

Porphyria diagnosis

Because porphyria can cause so many different symptoms, it can be hard to diagnose. Your doctor can talk to you and examine you, and will probably want to arrange urine or blood tests as well.

Genetic tests can be useful, too.

Since porphyria is rare, most doctors are unfamiliar with it and may not recognise the symptoms. Diagnosis can be delayed because porphyria mimics the symptoms and signs of various other medical conditions such as Guillain-Barre syndrome, eczema, multiple sclerosis and irritable bowel syndrome. Diagnostic tests may include:

• Physical examination
• Medical history
• Urine tests to check for elevated substances including porphyrins
• Blood tests to check for high levels of porphyrins in the plasma
• Stool sample to check for excreted porphyrins
• Genetic test.

Porphyria treatment

Acute porphyria

A health care provider treats acute porphyrias with heme or glucose loading to decrease the liver’s production of porphyrins and porphyrin precursors. A patient receives heme intravenously once a day for 4 days. Glucose loading involves giving a patient a glucose solution by mouth or intravenously. Heme is usually more effective and is the treatment of choice unless symptoms are mild. In rare instances, if symptoms are severe, a health care provider will recommend liver transplantation to treat acute porphyria. In liver transplantation, a surgeon removes a diseased or an injured liver and replaces it with a healthy, whole liver or a segment of a liver from another person, called a donor. A patient has liver transplantation surgery in a hospital under general anesthesia. Liver transplantation can cure liver failure.

Treatment of acute porphyria attacks focuses on providing rapid treatment of symptoms and preventing complications. Treatment may include:

• Pain medication
• Addressing the underlying cause – for example, prescribing antibiotics to treat an infection or ceasing a particular medication
• Medication called ‘hematin’, which is a type of heme the body can use
• Intravenous fluids and glucose
• Admission to hospital in severe cases.

There are plenty of ways to treat porphyria.

You can:

• avoid any drugs that may trigger an attack
• avoid alcohol
• protect your skin from the sun as much as possible
• eat carbohydrates frequently
• avoid strict diets.

Avoiding triggers may include:

• Not using medications known to trigger acute attacks. Ask your doctor for a list of safe and unsafe drugs.
• Not using alcohol or recreational drugs.
• Avoiding fasting and dieting that involves severe calorie restriction.
• Not smoking.
• Taking certain hormones to prevent premenstrual attacks.
• Minimizing sun exposure. When you’re outdoors, wear protective clothing, and use an opaque blocking sunscreen, such as one with zinc oxide. When
• indoors, use window filters.
• Treating infections and other illnesses promptly.
• Taking steps to reduce emotional stress.

Your doctor may also advise you about:

• medication to control pain, or any nausea or vomiting
• other medication to reduce the amount of porphyrin in the blood
• regular blood donation or blood-letting to reduce the amount of porphyrin in the blood.

Cutaneous porphyria

Treatment may include:

• Oral administration of activated charcoal, which helps to absorb excess porphyrins
• Daily supplementation with beta-carotene (vitamin A) as part of long-term treatment.
• A dietary supplement to replace vitamin D deficiency caused by avoidance of sunlight.
• Periodically drawing blood (phlebotomy) to reduce the iron in your body, which decreases porphyrins.
• Taking a drug used to treat malaria — hydroxychloroquine (Plaquenil) or, less often, chloroquine (Aralen) — to absorb excess porphyrins and help your body get rid of them more quickly than usual. These medications are generally used only in people who can’t tolerate a phlebotomy.

The most important step a person can take to treat a cutaneous porphyria is to avoid sunlight as much as possible. Other cutaneous porphyrias are treated as follows:

• Porphyria cutanea tarda. A health care provider treats porphyria cutanea tarda by removing factors that tend to activate the disease and by performing repeated therapeutic phlebotomies to reduce iron in the liver. Therapeutic phlebotomy is the removal of about a pint of blood from a vein in the arm. A technician performs the procedure at a blood donation center, such as a hospital, clinic, or bloodmobile. A patient does not require anesthesia. Another treatment approach is low-dose hydroxychloroquine tablets to reduce porphyrins in the liver.
• Erythropoietic protoporphyria. People with erythropoietic protoporphyria may be given beta-carotene or cysteine to improve sunlight tolerance, though these medications do not lower porphyrin levels. Experts recommend hepatitis A and hepatitis B vaccines and avoiding alcohol to prevent protoporphyric liver failure. A health care provider may use liver transplantation or a combination of medications to treat people who develop liver failure. Unfortunately, liver transplantation does not correct the primary defect, which is the continuous overproduction of protoporphyria by bone marrow. Successful bone marrow transplantations may successfully cure erythropoietic protoporphyria. A health care provider only considers bone marrow transplantation if the disease is severe and leading to secondary liver disease.
• Congenital erythropoietic porphyria and hepatoerythropoietic porphyria. People with congenital erythropoietic porphyria or hepatoerythropoietic porphyria may need surgery to remove the spleen or blood transfusions to treat anemia. A surgeon removes the spleen in a hospital, and a patient receives general anesthesia. With a blood transfusion, a patient receives blood through an intravenous (IV) line inserted into a vein. A technician performs the procedure at a blood donation center, and a patient does not need anesthesia.

Eating, Diet, and Nutrition

People with an acute porphyria should eat a diet with an average-to-high level of carbohydrates. The recommended dietary allowance for carbohydrates is 130 g per day for adults and children 1 year of age or older; pregnant and breastfeeding women need higher intakes.2 People should avoid limiting intake of carbohydrates and calories, even for short periods of time, as this type of dieting or fasting can trigger symptoms. People with an acute porphyria who want to lose weight should talk with their health care providers about diets they can follow to lose weight gradually.

People undergoing therapeutic phlebotomies should drink plenty of milk, water, or juice before and after each procedure.

A health care provider may recommend vitamin and mineral supplements for people with a cutaneous porphyria.

Home remedies

Be guided by your doctor, but general suggestions include:

• In all cases avoid known triggers – for example, don’t smoke.
• When out in the sun, wear sunglasses, a brimmed hat, a long-sleeved top and long pants. Apply SPF 30+ sunscreen to exposed skin areas.
• Protect your skin every day. For example, wear rubber gloves when handling chemicals or very hot water. Avoid perfumed soaps. Regularly apply barrier cream to the hands.
• Eat regular meals and avoid alcohol.
• You may like to consider wearing a medical alert bracelet or pendant, since surgery and some drugs can provoke symptoms.