Porphyria: The Rare Disease You Didn't Know Could Change Your Life Foreve

Porphyrias are disorders caused by a lack of enzymes involved in forming heme.

Heme is the compound that carries oxygen and gives blood its red color; it is a critical component of hemoproteins found in all tissues. Most heme is produced in the bone marrow to form hemoglobin. The liver also produces more significant amounts of heme, which is incorporated into cytochromes. Specific cytochromes in the liver oxidize chemical substances foreign to the body, including drugs, so that they are more easily excreted from the body.

Image: all porphyrias, except porphyria cutanea tarda, are hereditary.

Eight different enzymes are involved in heme formation. If one of these enzymes is missing, the chemical precursors of heme (including delta-aminolevulinic acid, porphobilinogen, and porphyrins) can accumulate in tissues, especially the bone marrow and liver, and then appear in the blood and be excreted in the urine and feces. Excess porphyrins make the skin more sensitive to sunlight because when exposed to light and oxygen, porphyrins form a charged, unstable form of oxygen that can damage the skin. Nerve damage is possible, expressed by pain or even paralysis, especially if delta-aminolevulinic acid and porphobilinogen accumulate.

The three most common porphyrias are:

porphyria cutanea tarda (late cutaneous porphyria),
acute intermittent porphyria and
erythropoietic protoporphyria.

They differ in terms of symptoms, detection tests, and treatment methods. However, they share some features with other, rarer porphyrias, including delta-aminolevulinic acid dehydratase deficiency, congenital erythropoietic porphyria, hepatoerythropoietic porphyria, hereditary coproporphyria, and porphyria variegata.

All porphyrias, except porphyria cutanea tarda, are hereditary. In a particular type of porphyria, the same enzyme is always affected, except that the mutations of this gene for the enzyme are different in people who are not members of the same family. Porphyrias can be classified in different ways. The classification based on the lack of a specific enzyme is most often used. It is also possible to classify according to whether the skin or nerves are primarily affected, and a third classification is based on the place of accumulation of chemical precursors in the formation of heme - in the liver or the bone marrow.

Laboratory test values in a person with porphyria are markedly disturbed. They must be selected and evaluated by an expert. If acute porphyria is suspected, the measurement of delta-aminolevulinic acid and porphobilinogen in the urine will be appropriate. Still, if cutaneous porphyria is suspected, the measurement of porphyrin in the blood plasma will be most appropriate. If there are deviations from normal during the screening laboratory tests, the specialist can order the determination of enzymes in the red blood cells.

Porphyria cutaneatarda

This is the most common form of porphyria, with typical skin involvement. Porphyria cutaneous late, as it is also called, occurs worldwide and is the only form of porphyria that is not hereditary. It is caused by the deficient activity of the liver enzyme uroporphyrinogen decarboxylase, which is involved in forming heme. Disorders occur due to the influence of iron, alcohol, estrogens, and hepatitis C virus infection.

Video content: Acute intermittent porphyria.

It also rarely occurs in people infected with HIV. Although the disorder is not hereditary, sometimes partial involvement of a gene inherited from one of the parents causes the development of this disease. In such a case, the disease is called familial late cutaneous porphyria.

Symptoms

Blisters appear on skin exposed to the sun (i.e., hands and face). Such skin is sensitive even to minor injuries. Scabs and permanent scars follow blisters. Skin damage is caused by porphyrins from the liver, which pass through the blood into the skin. Accelerated facial hair growth is possible.

Liver function is impaired, probably mainly due to hepatitis C virus infection or excessive alcohol consumption. After a long time, liver cirrhosis or liver cancer can even develop.

Diagnosis

According to porphyria cutaneetarde, diagnosis is confirmed by laboratory examination of porphyrins in blood plasma, urine, and feces. In any porphyria that causes skin involvement, a high concentration of porphyrins is found in the blood plasma, urine, and feces.

Treatment

This porphyria is the easiest to treat. It is usually used t. i. phlebotomy, a procedure in which half a liter of whole blood is withdrawn every 1 to 2 weeks. Thus, the level of iron in the body decreases, the level of porphyrins in the liver and blood plasma gradually decreases, and the skin condition ultimately improves. Usually, no more than 5-6 blood draws are needed, as more frequent draws would cause anemia. A more significant number of withdrawals is only necessary in case of repeated problems.

Image: Porphyria cutaneatarda is the most common form of porphyria.

Taking very low doses of chloroquine or hydroxychloroquine is also effective. These drugs remove excess porphyrins from the liver. Too high doses of drugs can cause porphyrins to be removed too quickly, which leads to transient worsening of the disease and liver damage. It is recommended to avoid alcoholic beverages.

Acute intermittent porphyria

Acute intermittent porphyria, which causes neurological symptoms, is the most common acute porphyria.

Acute intermittent porphyria is a liver porphyria caused by a deficiency of the enzyme porphobilinogen deaminase, also known as hydroxymethylbilane synthase. The enzyme deficiency is inherited from one of the parents, but the person who inherits the tendency to this disease never gets it. It occurs in all races but is slightly more common in people of Northern European descent.

Additional factors are needed, e.g., medications, hormones, or diet, for the disorder to manifest itself in the first place. Several drugs can lead to flares, including barbiturates, antiepileptics, and sulfonamide antibiotics; hormones include progesterone and related steroids; a small amount of carbohydrates and calories in the diet; and too many alcoholic beverages. Trigger factors for this disease include stress as a result of infection, other diseases, surgery, or mental stress. Several factors are usually interwoven, and we often cannot find the right one.

Symptoms

The disease usually starts after puberty and is more common in women than in men. Symptoms appear if the attack lasts several days. In some women, an attack of the disease develops in the second half of the menstrual cycle. The most common are abdominal pains, which can be so severe that the patient ends up on the operating table due to suspicion of an acute gastrointestinal disease.

Other symptoms include:

nausea, vomiting,
constipation or diarrhea and
Tension in the abdomen is due to the presence of gas.

The bladder may be affected, making it more difficult to pass urine. Symptoms during an attack include rapid heartbeat, high blood pressure, sweating, and restlessness. All these symptoms, including those related to the digestive system, result from nerve involvement. Nerves that control muscle function may be affected, causing muscle weakness, starting with the shoulder girdle muscles.

Image: acute intermittent porphyria is more common in women than in men.

Muscle weakness can spread to all muscle groups, including the respiratory muscles. Tremors and seizures may occur. Blood pressure can be elevated even after the attack. Recovery occurs after a few days, while it sometimes takes several months or years to improve muscle function fully.

Diagnosis

Severe digestive problems and nerve damage resemble more common diseases, e.g., acute intermittent porphyria. If the doctor thinks of the latter and measures an elevated level of metabolites in the formation of heme (i.e.,delta-aminolevulinic acid and porphobilinogen) in the urine, the diagnosis is confirmed. These metabolites are very high during the attack itself and frequent repeated attacks.

The metabolites can form porphyrins, which are reddish, and other substances, which are brownish. Thus, the color of the urine can change, especially if it is exposed to light. Depending on the change in the color of the urine, the doctor may suspect porphyria.

Treatment and prevention

Severe attacks of acute intermittent porphyria are treated with heme, which makes the patient sick to get into a vein. Scientists are developing a similar substance - heme arginate - with fewer side effects than hematin. The added heme is taken up by the liver and used instead of the one it cannot produce. Porphobilinogen and del-taaminolevulinic acid immediately decrease in the blood and urine, and symptoms improve within a few days. If we start the treatment too late, the recovery will be longer, and the nerve damage will be permanent.

Glucose into a vein or carbohydrate-rich food also works well, although heme treatment is most effective. Pain can be managed with medication as long as the patient responds favorably to treatment with heme or glucose. Among preventive measures, the doctor will advise the patient to avoid the factors that triggered the attack.

Video content: Acute intermittent porphyria - heme synthesis disorders.

Attacks can be prevented by proper nutrition and by avoiding the drugs that triggered the attack. Quick weight loss diets are extremely harmful. Attacks can be prevented with hemo, but the treatment scheme is not yet standardized. Attacks that occur just before menstruation could be prevented by adding a gonadotropin-releasing hormone analog, but the use of this drug is still in the testing phase.

Erythropoietic protoporphyria

Erythropoietic protoporphyria, in which protoporphyrin accumulates in the bone marrow, red blood cells, or blood plasma, causes skin hypersensitivity to light (i.e., photosensitivity). A deficiency of the enzyme ferrochelatase characterizes this hereditary porphyria. Deficiency of the enzyme is inherited from one parent. Accumulation of protoporphyrin in the bone marrow and blood is characteristic; the excess passes through the liver into the bile, and the latter is excreted in the feces.

Symptoms and diagnosis

The first symptoms appear in childhood. Pain and swelling occur shortly after the skin has been exposed to the sun. Because the blisters and scarring are unusual, it isn't easy to diagnose. It is further complicated by the fact that protoporphyrin is very poorly soluble and is not excreted in the urine.

Picture: the first symptoms appear in childhood.

The diagnosis can only be made when an elevated protoporphyrin level is found in the plasma and red blood cells. It is unknown why the severity of erythropoietic protoporphyria varies so much from person to person, even within the same family, since the gene mutation is the same.

Treatment

Avoid sunlight. Consuming sufficient beta-carotene causes a slight yellowing of the skin, making it less sensitive to sunlight. People with erythropoietic protoporphyria can form gallstones that contain protoporphyrin and often need to be surgically removed. A severe complication is liver damage, so severe that it requires a liver transplant.

Questions and answers

Which type of porphyria is the most common?

The most common type of acute porphyria is acute intermittent porphyria. The most common type of cutaneous porphyria—and the most common—is porphyria cutanea tarda, which affects about 5 to 10 out of every 100,000 people.

How is acute intermittent porphyria treated?

The treatment of acute porphyria attacks focuses on the rapid treatment of symptoms and the prevention of complications. This may include injections of hemin (Panhematin), a heme medicine, to limit the body's production of porphyrins and receiving a fluid containing sugar, also called glucose, through a vein or eating sugar, if possible. This ensures sufficient carbohydrates.

Are porphyrias curable?

Porphyria is a group of disorders that can cause nerve or skin problems. There is no cure, but you can get treatment to help manage your symptoms.

What causes erythropoietic protoporphyria?

Erythropoietic protoporphyria is a rare hereditary metabolic disorder caused by a deficiency of the enzyme ferrochelatase (FECH) resulting from changes (mutations) in the FECH gene.

Can animals also get porphyria?

Congenital erythropoietic porphyria (CEP) is a rare, hereditary disease of cattle, pigs, cats, and humans. It is the last of a significant but variable decrease in the activity of uroporphyrinogen III synthase (URO-synthase).

Sources and references

Porphyria: https://www.niddk.nih.gov
Porphyria: https://www.mayoclinic.org
Porphyria: https://www.webmd.com
Erythropoietic Protoporphyria and X-Linked Protoporphyria: https://rarediseases.org
Congenital Erythropoietic Porphyria: https://www.msdvetmanual.com