porphyria

Porphyria: description

Porphyries are rare and little known. They form a group of related metabolic diseases and express themselves mainly on the skin and nervous system.

Metabolism is the sum of all biochemical processes in the body where substances are built up, taken down and rebuilt. Enzymes are involved in these processes, each of which handles one step in the reaction chain. Many different metabolic pathways take place in the human body – one of them is the build-up of heme, which the body needs, among other things, for the red blood cells. The heme is made of a so-called porphyrin – an organic-chemical compound, of which there are different in nature – with an iron ion in the middle.

In the metabolic disorder porphyria heme can not be formed regularly because of an enzyme defect. The result is that the heme precursors build up because they can not be further processed. These precursors are also porphyrins – hence the name of the disease.

Why is porphyrin heme important?

Heme is an important component of hemoglobin – the red blood pigment in the red blood cells, which is responsible for the transport of oxygen in the blood: hemoglobin is composed of a protein complex with a central heme group. The iron ion from heme can bind molecular oxygen.

Heme is also part of the red muscle pigment myoglobin and the cytochrome. These are enzymes that are of crucial importance in the breakdown of pharmaceuticals.

Forms of porphyria

There are seven different porphyria forms – four acute and three non-acute variants.

The four acute porphyria forms are:

• the acute intermittent porphyria,
• the porphyria variegata,
• the hereditary coproporphyria and
• the very rare Doss porphyria.

They are called acute because they suddenly cause abdominal pain that can last for several days. In the case of Porphyria variegata and hereditary coproporphyria, sufferers additionally suffer from photosensitivity of the skin.

The three non-acute porphyria species show no acute abdominal pain and mainly affect the skin. They include:

• the porphyria cutanea tarda,
• the erythropoietic protoporphyria and
• the rare congenital erythropoietic porphyria (Günther’s disease).

The heme formation occurs mainly in the bone marrow, to a lesser extent also in the liver. Therefore, the seven forms of porphyria can also be divided into two groups, depending on the location where the heme precursors mainly accumulate due to an enzyme defect. Accordingly, one distinguishes:

• erythropoietic porphyrias (Bone marrow): erythropoietic protoporphyria, congenital erythropoietic porphyria (Günther’s disease)
• hepatic porphyrias (Liver): Acute intermittent porphyria, Porphyria variegata, Hereditary coproporphyria, Doss porphyria, Porphyria cutanea tarda

Porphyria: frequency

Only two forms, porphyria cutanea tarda and acute intermittent porphyria, occur in adulthood in adulthood. Erythropoietic protoporphyria is the most common childhood porphyria form. All other forms are very rare.

Porphyria: symptoms

Depending on where the enzyme defect is present, different porphyria symptoms manifest. The signs of the three most common porphyria forms are:

Acute intermittent porphyria (AIP)

Acute intermittent porphyria is characterized by a variety of symptoms, which makes it difficult for the doctor to make the right diagnosis. The severity of this form of porphyria varies greatly: while 90 percent of cases are asymptomatic (ie without discomfort), there are also cases of paralysis that can lead to death if the respiratory muscles are affected.

The disease mainly causes acute abdominal pain and neurological and psychiatric symptoms. These occur – as the term intermittently suggests – often shuddering. Most medications, hormonal changes (such as pregnancy, menstruation) or carbohydrate deficiency caused by diets or fasting such acute relapses. An acute episode usually only lasts for one to two weeks, but may persist much longer if symptoms of paralysis occur.

This is what an acute boost looks like:

• Violent colicky abdominal pain, usually localized in the lower abdomen, signaling the onset of a seizure.
• fever
• Vomiting and chronic constipation, which is difficult to treat.
• Reddish urine, which darkens after some time (dark spots in the underwear!)
• Neurological symptoms such as incomplete (paresis) or complete paralysis (paralysis), muscle weakness and sensory disorders (ie disorders in the area of ​​vision, hearing, taste, smell and sense of balance)
• Mental mood swings, delusions, coma and states of confusion (delirium)
• Cardiovascular problems such as palpitations (tachycardia) and high blood pressure (hypertension)

Porphyria cutanea tarda

In porphyria cutanea tarda, the heme precursors (porphyrins) accumulate in the liver, enter the blood and enter the skin. The result is a strong photosensitivity: The UV rays in sunlight form on the unprotected skin areas such as hands, face and neck blisters. Since the skin is also very vulnerable, such liquid-filled bubbles can form even with the smallest injuries and everyday work. The blisters burst and heal with the formation of bright, raised scars. Otherwise, the skin is stained brown by embedded porphyrins.

Those affected may also be overly hairy on the forehead, cheeks and around the eyes (hypertrichosis).

Patients also often suffer from liver disease (such as fatty liver or liver cirrhosis). The urine of the patients may be colored brown-red.

Erythropoietic Protoporphyria (EPP)

The skin is extremely sensitive to light: The porphyrin, which can not be further built up to heme due to the enzyme defect, circulates in the blood. Under the action of sunlight, it forms oxygen radicals in the skin that cause burn-like appearance of the skin with itching and pain. Just a few minutes of sunlight can trigger the skin symptoms. Even indirect light such as reflective surfaces can cause discomfort. The damaged skin can regenerate completely, but this can take hours to days. Glycoproteins can accumulate on the mostly unprotected skin areas, such as the nose or hands, causing the skin to thicken and coarsen.

In addition, some sufferers suffer from impaired liver function, which in ten percent of cases, develops into a chronic disease of the liver, cirrhosis of the liver.

Porphyria: causes and risk factors

The heme formation takes place via eight different reaction steps. Each step is facilitated by a specific enzyme, seven of the eight enzymes may be defective – porphyria is present.

The intermediates (heme precursors) formed in the reaction chain before the defective enzyme can not be processed further and accumulate. However, most of the production pathway of the heme is only partially blocked and is compensated by regulatory mechanisms, so that the heme formation at least partially works. Nevertheless, heme precursors (porphyrins) accumulate, which can cause various symptoms – usually in the form of porphyria attacks, triggered by certain factors such as infections or the ingestion of drugs.

Why make porphyrins sick?

The heme precursors, which can not be processed, deposit in the organs, especially in the skin and liver. In addition, the porphyrins are usually excreted in an increased amount with the stool and urine. A red or orange urine is therefore a typical symptom of some porphyria forms.

The accumulation of heme precursors leads in acute porphyrias above all to complaints in the area of ​​the abdomen and nervous system. In non-acute porphyria, on the other hand, skin changes are in the foreground.

Genetic alteration as a cause of porphyria

In porphyria, the genetic material (gene) of the defective enzyme is altered by a mutation. This mutation is inherited in most cases, generally autosomal dominant, that is independent of the sex chromosomes. Porphyria is usually only expressed together with external influences such as alcohol consumption, certain medications or infections.

In some cases, porphyria is acquired through poisoning (such as lead poisoning).

Acute intermittent porphyria (AIP)

Acute intermittent porphyria is the most common acute porphyria. Women are affected three times more often than men. As a rule, this form of porphyria is only noticed between the ages of 20 and 40 years.

In acute intermittent porphyria, the third enzyme in the heme production path, the porphobilinogen deaminase, is defective. This defect is inherited autosomal dominant. However, complaints usually only appear when factors such as certain medications, alcohol or infections are added. These then trigger an acute disease spurt (“intermittent” means, occurring intermittently).

Porphyria cutanea tarda

The porphyria cutanea tarda is the most common form of porphyria and is also inherited as an autosomal dominant. It can be heterozygous (genetic defect on one of the two paired chromosomes) or homozygous (genetic defect on both chromosomes) inherited. Men are twice as likely to be affected as women. The disease is usually noticeable from the age of 40 years.

In this form of porphyria, the fifth enzyme, uroporphyrinogen decarboxylase, is affected by the disorder. People with this defect often do not notice the disease. Only when the liver is heavily used, complaints are triggered. Alcohol is responsible for overuse of the liver in two-thirds of the cases. But there are also other triggers such as medications, such as estrogens in the contraceptive pill.

Erythropoietic Protoporphyria (EPP)

In rare erythropoietic protoporphyria, the enzyme defect lies in the last step of heme formation, the incorporation of the iron ion. The consequence is above all a strong photosensitivity of the skin. Erythropoietic protoporphyria often occurs for the first time in childhood.

Porphyria: examinations and diagnosis

Due to the complexity of the disease and the many-sided symptoms, it may also be for one experienced doctor difficult to be the right diagnosis. Especially important are the typical porphyria symptoms as well as information about similar diseases in relatives. For accurate porphyria diagnosis, blood, urine and stool for porphyrins are examined. The best way to do this is when the person is experiencing ailments, as the values ​​in the course of the disease can change and even drop to a normal level. Further important diagnostic steps in the diagnosis of porphyria:

Acute intermittent porphyria (AIP)

In acute intermittent porphyria the urine turns red to dark red on prolonged standing. This proof succeeds however only with two thirds of the cases. Another screening test is the reverse Ehrlich aldehyde sample. One drop of urine is added to one milliliter of Ehrlich’s reagent. If there is acute intermittent porphyria, the result is a cherry red color.

Porphyria cutanea tarda

Characteristic is an enlarged liver, which is usually palpable. When ultrasound examination is usually a fatty liver or liver cirrhosis to recognize. In addition, a liver biopsy can be revealing. A small tissue sample of the liver is taken under local anesthesia with a hollow needle. Under a UV lamp, the tissue sample fluoresces red in Porphyria cutanea tarda. When subsequently examined by microscope, an increased accumulation of iron (iron storage disease = siderosis), fatty liver, chronic liver inflammation or cirrhosis of the liver can sometimes be detected.

Erythropoietic Protoporphyria (EPP)

The symptoms described often already give rise to the suspicion of erythropoietic protoporphyria. This suspicion can be confirmed by a blood analysis. It examines heparin blood, that is, uncoagulated blood from red blood cells and blood plasma, to free protoporphyrin, a precursor of heme. Sometimes stool samples are also tested for protoporphyrin.

Porphyria: treatment

It is important to differentiate the different porphyrias as they are treated differently. For all: The respective enzyme defect is genetically determined and is therefore not curable. The therapy is therefore symptomatic, that is, only the symptoms can be alleviated. The aim is also to avoid triggering factors (exposure prophylaxis).

Acute intermittent porphyria (AIP)

If diagnosed and severe relapses, sufferers may need to be under intensive care because of the risk of respiratory paralysis. Triggers of an acute push such as certain medications must be discontinued. In addition, glucose or heme arginine is infused, resulting in the elimination of enriched heme precursors. For reassurance and against the pain, patients are treated, for example, with salicylates and morphine derivatives. For tachycardia and high blood pressure help so-called b-receptor blocker (beta blocker) and reserpine.

Porphyria cutanea tarda

With Porphyria cutanea tarda, a consistent renouncement of the triggering factors such as alcohol and estrogen (as in the pill) can improve the symptoms. In addition, sufferers should protect themselves with sunscreen and clothing from the sun.

It may also be helpful to have a bloodletting in which 500 milliliters of blood are drained once a week. The aim is to flush out the accumulated porphyrin from the liver. With a total bleeding of four to eight liters, the condition of the patients normalizes in most cases. Patients should drink at least one and a half liters daily in order to compensate for the fluid loss. If liver cirrhosis is present, no bloodletting should be performed, as it would cause too many proteins to be lost.

For severe cases, chloroquine therapy is recommended. Chloroquine, originally a drug used to treat malaria, binds porphyrin, which is excreted by the kidneys. Thus, porphyrin can be well removed from the body. With good liver function, a chloroquine dose of 500 milligrams per day for one week is recommended.

Erythropoietic Protoporphyria (EPP)

Important measures are light protection through clothing and special sunscreen creams as well as the avoidance of triggering factors (such as alcohol, medication).

A phototherapy with the dermatologist in the spring can make the skin more tolerant of sunlight: The skin is gently irradiated several times a week with artificial UV light. This makes her a little thicker and gives her a light complexion.

Some sufferers may relieve the symptoms of erythropoietic protoporphyria by taking beta-carotene, an orange natural dye. It can neutralize the reactive oxygen in the skin that is created by light and improve the symptoms. By taking the skin turns but usually slightly orange.

The drug Afamelanotide is a new therapy and stimulates the tanning of the skin. It is increasingly the skin pigment melanin formed, which is stored in the skin. High levels of melanin in the skin can increase the amount of time the sun can expose the person. Afamelanotide shows good results and can significantly improve the quality of life. However, this drug is not yet approved in Germany.

If liver cirrhosis develops, a liver transplant must be considered.

Porphyria: prevention

Porphyria can not be prevented because the disease is genetically determined. However, sufferers can do something themselves to prevent porphyria symptoms.

Acute intermittent porphyria (AIP)

Most acute relapses can be avoided by taking consistent precautions.

drugs: Certain medications can trigger an acute episode. Therefore, talk to your doctor before taking any medication and also when using home remedies or plant substances. It is best to completely abstain from medication. If this is not possible, for example, in the case of a serious illness, the physician will prescribe suitable medications after weighing the benefits and risks and with the agreement of a porphyria specialist.

alcohol: Patients are strongly advised against any alcohol intake. For some it can be very difficult to give up alcohol in the long term. However, you have to keep in mind that every boost can potentially be life-threatening.

nutrition: Diets or fasting can lead to an acute boost. It is therefore very important to pay attention to a regular diet and to maintain its weight. Patients with severe porphyria who have already had multiple relapses should be assisted by their doctor and nutritionist.

Porphyria cutanea tarda and erythropoietic protoporphyria (EPP)

Important in both porphyria forms is to avoid the sun as much as possible:

dressA simple sun protection measure is to wear long-sleeved, tightly woven clothing, a hat, closed shoes and gloves.

suncream: Normal sunscreens are not suitable because they absorb the light in the UV range, but not the blue portion of the visible light, which also damages the skin. You should therefore only use special sunscreen creams based on titanium dioxide and zinc oxide as these protect against UVA, UVB and visible light.

These simple measures can reduce the risk of porphyria. Most sufferers only have one to two relapses in their lives. The risk of a relapse decreases with age – however, porphyria never disappears completely.

Porphyria: disease course and prognosis

The severity of porphyria varies. For most sufferers a largely normal life is possible if they pay attention to certain things. Others suffer from severe, painful photosensitivity and liver dysfunction.

Acute intermittent porphyria (AIP)

Most sufferers who experience one or more relapses recover completely and only have to take care of a few precautions. In less than ten percent of cases, recurrent episodes often occur. If it comes to paralysis, it can take several weeks to many months before they regress.

Erythropoietic Protoporphyria (EPP)

Patients with EPP should go to the doctor regularly (at least once a year) to have their blood tested for possible damage from accumulated porphyrin. This is rare, but should be recognized as early as possible, because erythropoietic protoporphyria is fatal in ten percent of cases.

Porphyria cutanea tarda

The course of this porphyria form is usually favorable, but depends on how much the liver is damaged and whether certain drugs (as a trigger) consistently avoided.

Patients with this form of porphyria have an increased risk of liver cell cancer.