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Porphyria: symptoms, forms and treatment

by Josephine Andrews
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Porphyria is a group of rare metabolic diseases that are associated with impaired formation of the red blood pigment heme. Typical porphyria symptoms are colicky abdominal pain and severe photosensitivity of the skin. Most porphyrias are hereditary and can therefore only be treated symptomatically. Learn more about porphyria here.

ICD codes for this disease:

ICD codes are internationally valid codes for medical diagnoses. They can be found, for example, in doctor’s letters or on certificates of incapacity for work.

E80

Brief overview: porphyria

  • Symptoms: Depending on the form, severe abdominal pain, gastrointestinal problems, muscle weakness and paralysis, cardiovascular problems, high sensitivity of the skin to light , reddish urine
  • Forms: There are seven different forms, four of which are acute, ie lead to very sudden symptoms.
  • Causes: Porphyria is caused by changes in the genetic material, triggers include, for example, alcohol, certain medications and infections.
  • Diagnosis: Detection of porphyrins in blood, urine or stool, depending on the type, further investigations such as testing for urine discoloration and ultrasound or biopsy of the liver
  • Treatment: The most important thing is to consistently avoid the triggers (e.g. alcohol, medication). Depending on the form, various medications and consistent skin protection can also help.
  • Course: varies depending on the form, but a largely normal life is usually possible if those affected consistently follow certain precautionary measures and avoid the triggers
  • Prevention: Since the disease is genetic, it is not possible to prevent it. However, flare-ups can often be prevented with simple measures.

What is porphyria?

Porphyrias are a group of rare, related metabolic diseases. They manifest themselves primarily in complaints of the skin and nervous system.

The term metabolism describes the sum of all biochemical processes in the body in which substances are built up, broken down and converted. Enzymes are involved in these processes . These are specialized proteins that each process a step in the reaction chain.

Many different metabolic pathways take place in the human body – one of them is the build-up of what is known as heme. This is a chemical compound that the body needs, among other things, for the red blood cells or the red blood pigment they contain.

Heme consists of a so-called porphyrin – an organic chemical compound of which there are different in nature. In the case of the metabolic disease porphyria, the body is unable to form it regularly due to an enzyme defect. The result is that the heme precursors build up because the organism is not able to process them further.

Due to their chemical structure, these precursors also belong to the porphyrins and have given their name to the porphyrias. In particular, the porphyrins accumulate in the skin and liver.

Why is the porphyrin heme important?

Heme is an important component of hemoglobin – the red blood pigment in red blood cells. Hemoglobin is composed of a protein complex with a central heme group. The iron ion contained in heme binds molecular oxygen. This enables the red blood cells to supply the organism with oxygen via the blood.

Heme is also a component of the red muscle pigment myoglobin and the cytochromes. These are enzymes that, among other things, play a crucial role in the breakdown of drugs.

Porphyria: frequency

There are seven different forms of porphyria, but only two, porphyria cutanea tarda (PCT) and acute intermittent porphyria (AIP), occur with any significant frequency in adulthood. About two in 100,000 people have PCT, and about one in 1,000,000 people have AIP.

Erythropoietic protoporphyria is the third most common porphyria overall, affecting approximately one in 200,000 people. All other forms are very rare.

What are the symptoms of porphyria?

Depending on which of the eight enzymes involved in heme formation is defective, different porphyria symptoms manifest themselves.

Symptoms of 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 only becomes noticeable between the ages of 20 and 40. Acute intermittent porphyria is characterized by a variety of symptoms, which is why it is often difficult for the doctor to make the correct diagnosis.

The severity of AIP varies greatly: While 90 percent of cases are asymptomatic (ie without symptoms), there are also cases of illness with paralysis. If the respiratory muscles are affected, this can lead to death.

The disease mainly causes acute abdominal pain as well as neurological and psychiatric symptoms. As the term intermittently suggests, these often occur intermittently. Alcohol, medication, hormonal changes such as pregnancy and menstruation, stress or a lack of carbohydrates caused by dieting or fasting usually trigger such acute flare-ups.

An acute attack usually lasts one to two weeks. If symptoms of paralysis occur, this period of time may be significantly longer.

Typical symptoms of an acute attack are:

  • Severe colicky abdominal pain, especially in the lower abdomen (often signaling the onset of a flare-up)
  • fever
  • Vomiting and chronic constipation that is difficult to treat
  • Reddish urine that gets darker over time (dark spots on underwear!)
  • Neurological symptoms such as incomplete or complete paralysis, muscle weakness and disorders of the senses and the sense of balance (sensory disorders)
  • Mood swings, delusions, coma and states of confusion (delirium)
  • Cardiovascular problems such as racing heart (tachycardia) and high blood pressure (hypertension)

Symptoms of porphyria cutanea tarda (PCT)

Porphyria cutanea tarda is one of the chronic hepatic porphyrias and is the most common form of porphyria overall. It occurs about twice as often in men as in women and usually becomes noticeable from the age of 40.

However, problems usually only arise when the liver is under heavy strain. The heme precursors (porphyrins) then accumulate in the liver, enter the blood and thus penetrate the skin. The result is a strong sensitivity to light: The UV rays in sunlight cause blisters to form on unprotected skin, for example on the hands, face and neck.

Since the skin is also very vulnerable, such fluid-filled blisters form even with the smallest injuries and everyday work. The blisters burst and form bright, raised scars as they heal . Otherwise, the skin is brownish in color due to stored porphyrins.

In addition, some sufferers have excessive hair on the forehead, cheeks and around the eyes (hypertrichosis). The urine may be colored brown-red due to the porphyrins excreted in the urine.

Symptoms of Erythropoietic Protoporphyria (EPP)

EPP begins in childhood. In this form of porphyria, the skin is extremely sensitive to light, since the accumulating porphyrins form oxygen radicals in the skin under the influence of sunlight. These are aggressive chemical compounds that lead to burn-like symptoms with itching and pain.

A few minutes of sunlight are often enough to trigger the skin symptoms. Indirect light, such as from reflective surfaces, also causes problems. Although the damaged skin is able to regenerate itself completely, this may take hours or days.

What forms of porphyria are there?

Heme formation occurs in eight different reaction steps. Each requires a specific enzyme. In seven of these eight enzymes, an enzyme effect leads to porphyria.

Experts therefore distinguish between seven different forms of porphyria. Four of them are acute, the other three are non-acute variants. Acute means that the symptoms typical of the disease appear very suddenly.

The four acute forms of porphyria are:

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

In contrast, the three non-acute types of porphyria do not show acute abdominal pain and mainly affect the skin. They include:

  • porphyria cutanea tarda,
  • erythropoietic protoporphyria and
  • the rare congenital erythropoietic porphyria (Morbus Günther).

Heme formation takes place mainly in the bone marrow and to a lesser extent in the liver. Therefore, the seven forms of porphyria can instead be divided according to where the heme precursors mainly accumulate due to an enzyme defect:

  • erythropoietic porphyrias (bone marrow): erythropoietic protoporphyria, congenital erythropoietic porphyria (Morbus Günther)
  • Hepatic porphyrias (liver): acute intermittent porphyria, porphyria variegata, hereditary coproporphyria, Doss porphyria, porphyria cutanea tarda

Causes and risk factors

The cause of all forms of porphyria is a change (mutation) in the part of the genetic material that contains the blueprint for one of the enzymes involved in heme formation. in most cases, one parent passes the mutation on to their offspring. Inheritance is usually autosomal dominant.

Autosomal means that the affected gene is not on the two sex chromosomes. Whether the child of an affected parent falls ill does not depend on its gender. Dominant means that it is sufficient if only one parent passes on a defective gene to the child. It is therefore not necessary for both gene copies to be affected in order to trigger the disease.

However, porphyria usually only manifests itself when certain external influences are added, such as alcohol consumption, nicotine consumption, certain medications, hormonal contraceptives, stress or infections. Infections with the hepatitis C virus and the human immunodeficiency virus (HIV) play a particularly important role in porphyria cutanea tarda.

In some cases, poisoning (such as lead poisoning) also leads to porphyria.

In most cases, the heme production pathway is only partially blocked in porphyria, since certain regulatory mechanisms ensure that heme formation works at least partially. Nevertheless, heme precursors (porphyrins) accumulate and cause corresponding symptoms.

investigations and diagnosis

Due to the complexity of the disease and the variety of symptoms, it is sometimes difficult even for an experienced doctor to make the correct diagnosis. The typical porphyria symptoms and information about similar symptoms in relatives are particularly important.

For an accurate porphyria diagnosis, the doctor checks whether the blood, urine, or stool contain porphyrins. It is best to carry out the examination when the person concerned is experiencing symptoms, as the values ​​​​change over the course of the disease and sometimes even drop to a normal value.

Other important diagnostic steps in the clarification of a porphyria depend on the respective porphyria form.

Acute intermittent porphyria

In acute intermittent porphyria, the urine turns red to dark red after standing for a long time. However, this proof is only successful in two thirds of the cases.

Another test is the reverse Ehrlich aldehyde test. The doctor adds a drop of urine to one milliliter of a special solution, the so-called Ehrlich reagent. If acute intermittent porphyria is present, the color will be cherry red.

Porphyria cutanea tarda

An enlarged liver, which is usually palpable, is characteristic. Fatty liver or cirrhosis of the liver can usually be seen in the ultrasound examination . Sometimes a liver biopsy is revealing. The doctor takes a small tissue sample with a hollow needle under local anesthesia.

Under a UV lamp, the tissue sample fluoresces red in porphyria cutanea tarda. The microscopic examination sometimes reveals an increased accumulation of iron (iron storage disease = siderosis) or signs of fatty liver, chronic liver inflammation or liver cirrhosis. Liver values ​​​​are often changed in a blood test.

Erythropoietic protoporphyria 

The symptoms described often lead to the suspicion of erythropoietic protoporphyria. This suspicion can be confirmed by a blood analysis. The doctor examines the blood for free protoporphyrin, a precursor of heme. Protoporphyrin can also be detected by means of a stool sample.

treatment

It is important to distinguish the different porphyrias because the treatment varies. The following applies to all: The respective enzyme defect is genetically determined and is therefore not curable. The therapy is therefore symptomatic, which means that only the symptoms can be alleviated. The aim is also to avoid triggering factors (exposure prophylaxis).

Acute intermittent porphyria

If the diagnosis is confirmed and the flare-ups are severe, it is often necessary to monitor those affected in intensive care because there is a risk of respiratory paralysis. It is particularly important to eliminate the triggers of an acute flare-up, for example to discontinue certain medications.

In addition, the doctor administers glucose or heme-arginine via an infusion . This causes the body to excrete the accumulated heme precursors. In the case of abdominal colic, those affected receive suitable medication such as painkillers and antispasmodic drugs. Beta blockers, for example, help against heart palpitations and high blood pressure.

Since 2020, a causal therapy has also been available for the first time. The active ingredient inhibits the enzyme that enables the very first step in heme production. By doing so, it prevents the harmful intermediates responsible for the porphyria symptoms from forming and piling up.

Porphyria cutanea tarda

In the case of porphyria cutanea tarda, it often helps to consistently avoid the triggering factors such as alcohol and estrogen (as in the pill ). In addition, those affected should protect themselves from the sun with sunscreen ointments and clothing.

Bloodletting, in which the doctor drains 500 milliliters of blood once a week, may be helpful. The aim is to flush out the accumulated porphyrin from the liver. With a bloodletting of four to eight liters in total, the condition returns to normal in most cases.

In severe cases, chloroquine therapy is recommended. Chloroquine, originally a drug used to treat malaria, binds the porphyrin. In this form, the body is able to excrete it through the kidneys.

Since those affected should avoid sunlight, they often develop a vitamin D deficiency , because vitamin D is mainly formed in the skin under the influence of sunlight. In this case, the doctor also prescribes a vitamin D supplement.

Erythropoietic protoporphyria

Important measures are sun protection through clothing and special sun protection creams from an early age. In addition, those affected should avoid the triggering factors (e.g. alcohol, medication) as much as possible.

Phototherapy by a dermatologist in spring makes the skin more tolerant of sunlight: the doctor carefully irradiates the skin with artificial UV light several times a week.

In rare cases, the symptoms of erythropoietic protoporphyria can be relieved by taking beta-carotene, an orange natural pigment. It helps to neutralize the reactive oxygen in the skin caused by light and to improve the symptoms. When ingested, the skin usually turns slightly orange.

The active ingredient afamelanotide enables a new therapy. It stimulates the formation of the skin pigment melatonin and thus skin tanning. A high level of melanin in the skin often increases the amount of time that the affected person can be exposed to the sun. Afamelanotide shows good results and often leads to a significantly improved quality of life.

Some people with EPP have impaired liver function. Those affected then receive medication that supports the liver. Liver cirrhosis, a chronic disease of the liver, develops in about two to five percent of cases. In this case, a liver transplant may be necessary.

Vitamin D deficiency is also common in EPP, which can be compensated for with a vitamin D supplement.

Course of the disease and prognosis

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

Acute intermittent porphyria

Most people who experience a flare-up or flare-ups make a full recovery and only need to take a few precautions. Frequently recurring flare-ups occur in less than 10 percent of cases. If symptoms of paralysis occur, it often takes several weeks to many months for them to recede.

Erythropoietic protoporphyria 

Patients with EPP should see their doctor regularly (at least once a year) for blood tests to check their liver for possible damage from accumulated porphyrin. This is important, among other things, because those affected have an increased risk of liver cancer. Kidney damage is also possible later in the course of the disease.

Porphyria cutanea tarda

The course of this form of porphyria is usually favorable, but depends on how badly the liver is damaged and whether those affected consistently avoid certain medications as a trigger.

Prevent

Porphyria cannot be prevented because the disease is genetic. However, those affected have the opportunity to do some things themselves to avoid or alleviate porphyria symptoms.

Acute intermittent porphyria

Most acute flare-ups can be avoided by taking consistent precautions.

Medications : Certain medications trigger acute flare-ups. Those affected should therefore speak to their doctor before taking any medication or using home remedies or herbal substances.

Alcohol : It is advisable for sufferers to avoid alcohol as much as possible.

Diet : Diets or fasting sometimes lead to an acute flare-up. It is therefore very important to pay attention to a regular diet and to maintain your weight. People with severe porphyria who have had multiple flare-ups should seek support from their doctor and a nutritionist.

Porphyria cutanea tarda and erythropoietic protoporphyria

With both forms of porphyria, it is important to avoid the sun as much as possible:

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

Sun cream : Normal sun creams are not suitable because they absorb the light in the UV range, but not the blue part of the visible light, which also damages the skin. Those affected should therefore only use special light protection creams based on titanium dioxide and zinc oxide, as these protect against UVA, UVB and visible light.

These simple measures reduce the risk of a porphyria flare-up. Most sufferers only have one or two flare-ups in their lifetime. The risk of having a relapse decreases with age, but the porphyria never goes away completely.

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