Contents
What is porphyria?
Porphyrias are a group of disorders caused by the accumulation of proteins used in the production of red blood cells.
Heme is the name given to the chemical compound that gives the blood a red color and is essential for several proteins in the body, including hemoglobin , which transports oxygen to cells.
Heme is produced in the bone marrow and liver in a process controlled by 8 different enzymes . These enzymes transform one compound into another until heme production is complete.
Porphyria, a genetic disease, occurs when any of the last 7 enzymes that work in the production of heme is deficient or when the first of them has an increase in activity, causing an accumulation of precursor compounds in heme.
This buildup causes symptoms that vary depending on which enzyme is deficient.
When the first enzyme is deficient, the disease is caused anemia , sideroblastic not porphyria.
How does it work
Porphyria is a complex disease. The production of heme , which is essential for blood, goes through eight stages and functions as an assembly line for a factory.
Enzymes
Enzymes are substances that accelerate chemical reactions. They are so important that, without them, some reactions hardly happen.
During the production of heme, 8 enzymes are needed. To facilitate understanding we will call the enzymes 1, 2, 3 and so on, up to the enzyme 8.
Enzyme 1 takes a mixture of glycine and succinylcoenzyme A , two substances needed to start the process. It transforms this mixture into aminolevulinic acid , the first precursor to heme .
Then, enzyme 2 turns aminolevulinic acid into porphobilinogen and so on.
These substances are called heme precursors and bear that name because, through their chemical transformations, the body creates heme.
Precursors
The seven precursors, which are called porphyrins , are as follows:
- Aminolevulinic acid;
- Porphobilinogen;
- Hydroxymethylbilane;
- Uroporphyrinogen III;
- Coproporphyrinogen III;
- Protoporfirinogênio IX;
- Protoporfirina IX.
Each of them is transformed, by enzymes, into the next compound. Finally, protoporphyrin IX is transformed into heme .
Accumulation of precursors
As on an assembly line, an employee can only assemble a part if the previous employee has done his or her job.
In the case of enzymes it is the same. The protoporphyrin IX can be transformed into heme, before that, protoporphyrinogen IX is converted into protoporphyrin IX .
If one of the enzymes is not present or is deficient, the assembly line slows down. There will still be heme production, but it will be reduced.
However, this is not the problem. What causes the problem is the accumulation of precursors .
Imagine that enzyme 4 in a person is deficient. In this case, it is not transforming hydroxymethylbilane into uroporphyrinogen III .
There will be a lack of uroporphyrinogen III and subsequent substances, but the previous enzymes are still working. This means that hydroxymethylbilane will be left over .
All that material is still being produced, but the broken chain allows it to accumulate. The precursors of heme are toxic and its accumulation is what causes the symptoms of porphyria.
Feedback
In addition, there is the feedback factor .
Feedback is a process by which the system measures responses to acquire information. In the case of the body and porphyria, the body can measure the need to produce one substance based on the amount of another substance present.
If there is an excess of precursor A, the body can identify this and cease production, which is beneficial.
However, the opposite can happen. He can identify the lack of precursor B and think it is because there is not enough precursor A, further increasing production. The result is an even greater accumulation.
What defines the symptoms of porphyria is which enzyme is deficient and which precursor is being accumulated.
Types
There are several types of porphyrias, as their symptoms vary according to which enzyme is having problems in the production of heme. However, although the enzymatic differentiation is more precise, the most common and simple is that they are divided into two groups, based on clinical characteristics.
Remembering that it is possible to have more than one porphyria at the same time, including the two different types.
Acute porphyria
Acute porphyrias have their symptoms manifested intermittently and irregularly. These symptoms can affect the abdominal region, in addition to altering the mental and neurological state.
In some cases, they also have cutaneous symptoms, but due to their other symptoms, it is still classified as acute and not cutaneous.
This type of porphyria arises due to a deficiency of the following enzymes:
- Delta-aminolevulinic acid dehydratase (ALAD) (Enzyme number 2);
- Porphobilinogen deaminase (Enzyme number 3);
- Coproporphyrinogen oxidase (Enzyme number 6);
- Protoporphyrinogen oxidase (Enzyme number 7).
Porphyria cutanea
Cutaneous porphyria has continuous or intermittent symptoms involving the skin, which can become fragile, create blisters and be sensitive to light.
The enzymes that cause this type of condition when deficient are:
- Uroporphyrinogen III cossintase (Enzyme number 4);
- Uroporphyrinogen decarboxylate (Enzyme number 5);
- Ferroquelatase (Enzyme number 8).
The first enzyme in the heme production line, the specific erythroid of delta-aminolevulinic synthase-2 (ALAS 2) does not cause porphyria when deficient, but when there is an increase in its activity. The symptoms are identical to those of the deficiency of ferroquelatase (enzyme number 8).
When ALAS 2 is deficient, the disease caused is sideroblastic anemia , not porphyria.
Disease names
The porphyrias created by each of these deficiencies have different names. The table below shows the deficiency of each of the enzymes followed by the name of the created porphyria.
- Enzyme number 1 : Erythroid specific for delta-aminolevulinic acid synthase-2 (ALAS 2);
- Enzyme number 2 : Delta-aminolevulinic acid dehydratase (ALAD) – disease caused : Porphyria ALAD;
- Enzyme number 3 : Porphobilinogen deaminase – disease caused : Acute intermittent porphyria (PAI);
- Enzyme number 4 : Uroporphyrinogen III cossintase – disease caused : Congenital erythropoietic porphyria;
- Enzyme number 5 : Uroporphyrinogen decarboxylase – disease caused : Porphyria cutanea tarda and porphyria hepatoeritropoietica;
- Enzyme number 6 : Coproporphyrinogen oxidase – disease caused : Hereditary coproporphyria;
- Enzyme number 7 : Protoporphyrinogen oxidase – disease caused : Porphyria variegata;
- Enzyme number 8 : Ferroquelatase – disease caused : Erythropoietic protoporphyria.
Causes
The causes of porphyria are mostly hereditary. There are recessive and dominant variations . Let’s explain.
A little bit of genetics
Humans have 23 pairs of chromosomes, one of which defines the person’s biological sex. The other 22 pairs are called autosomes and will define body characteristics such as height, eye color, hair and everything else.
The sperm carries half of the genetic load of man. That is, it does not take the 23 pairs, but only 23 chromosomes alone. The egg does the same, taking 23 chromosomes from the woman. When they come together to create the baby that will be born, genetics are formed in pairs of the child with the sum of the parents’ chromosomes.
Porphyrias are caused by a genetic alteration in one of the autosomal pairs (which of the pairs varies, depending on which is the variation of the disease).
When it is recessive, it is necessary for both chromosomes of the affected pair to be changed, but if it is dominant, it is enough that one of them is so for the disease to manifest.
Recessive
For a recessive disease to manifest, the two chromosomes in the pair must have the change. If only one of them is changed, the disease does not appear.
Imagine that both parents of a child have only one of the chromosomes altered.
- Mother: Altered 1 – Normal 1;
- Parent: Normal 2 – Changed 2.
Neither of them has the disease, but they can pass it on to their children. Of these chromosomes, only one of each will go to the child. It has four possible combinations:
- Normal 1 – Normal 2;
- Normal 2 – Altered 2;
- Altered 1 – Normal 1;
- Changed 1 – Changed 2;
In the first combination, there is no altered gene and that person cannot pass the disease forward, nor will it manifest it. In the two combinations of the environment, the child is like his parents: he does not manifest the disease, but he has the possibility of passing it on to his children.
The fourth combination is a child who manifests the disease. If that child has children, they will all carry at least one of the altered genes.
If only one parent has the altered gene, none of the children will manifest the disease as they will have, at most, only one altered gene.
Dominant
When the disease has a dominant characteristic , it is enough that one of the chromosomes in the pair is altered for it to manifest. Let’s show it again:
- Mother: Normal 1 – Normal 2;
- Parent: Normal 1 – Changed 2.
In this case, only the father has the altered gene. But as we are dealing here with the dominant version of the disease, it manifests porphyria. The son of this couple has 4 possibilities:
- Normal 1 – Normal 1;
- Normal 1 – Altered 2;
- Normal 2 – Normal 1;
- Normal 2 – Altered 2.
The difference here is that just one altered gene is enough for the disease to appear. The first and third combinations do not have the disease nor are they able to pass it on to the next generation, but the second and fourth combinations manifest the condition and transmit it.
Porphyrias
The deficiencies of number 2, 4, 5 and 8 enzymes are recessive. This means that, in order for the person to present the disease, both parents need to have the gene altered and pass this gene on to the child.
The deficiencies of number 3, 5, 6 and 7 enzymes have a dominant character. Only one parent needs to pass on the defective gene for it to manifest.
It is important to note that enzyme 5 deficiency can be both dominant and recessive. More than one genetic change can cause deficiency of this enzyme. When this change is recessive , it causes hepatoerthropoietic porphyria , whereas when it is dominant, it causes late cutaneous porphyria .
Porphyria cutanea tarda (PCT)
There is a type of porphyria that is not transmitted by parents. The porphyria cutanea tarda , in 25% of cases, is caused by a dominant gene. However, there is the sporadic type , which has no known genetic correlation, that is, it is not transmitted by the parents, but caused by a random mutation. This type is responsible for 75% of PCT cases.
It is also possible to acquire this specific type of porphyria through exposure to the chemical compounds hexachlorobenzene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (Seveno dioxin).
Both are extremely toxic and capable of reducing the activity of the uroporphyrinogen decarboxylase enzyme, but these substances cannot be easily found.
Hexachlorobenzene is a product of prohibited production in several countries, including Brazil, and Seveno dioxin is produced only in the laboratory for research.
Groups of risk
The risk group includes people whose relatives have porphyria. As it is a genetic disease, it is not infectious and it is not possible for someone without porphyria to catch the disease. It is possible to develop porphyria cutanea tarda without the parents having the altered gene, but it is not possible to predict who will do it – the person is born with the disease.
Symptoms
The classification of porphyrias in cutaneous and acute is due to their symptoms. There are specifications for each of them, but in general, we can consider:
Cutaneous porphyrias
Although there are cases in which symptoms are intermittent, cutaneous porphyrias are usually chronic and present with symptoms all the time. The skin is fragile and can create blisters, especially if exposed to sunlight.
There is also an increase in the amount of hair on patients’ bodies and changes in gums that can leave teeth more exposed.
There are researchers who believe that porphyrias may have been the beginning of the legends of vampires and werewolves due to their symptoms. Sensitivity to sunlight and hair growth may have contributed to this, in addition to other symptoms belonging to the category of acute porphyrias.
The most common type of porphyria cutanea is porphyria cutanea tarda .
Porphyria cutanea tarda
One of the two most common types of the disease, porphyria cutanea tarda has chronic blistering lesions on the skin .
Acute porphyrias
Due to the accumulation of porphobilinogen in the blood, almost all acute porphyrias have reddish urine. The color may become even more evident after exposure to the sun.
This symptom may also have contributed to the legends of vampires and werewolves at a time when unknown and chronic diseases were a mystery.
In addition, acute porphyrias can cause severe pain, hallucinations, weakness, seizures , motor and sensitivity problems, among others.
The most common type of acute porphyria is intermittent acute porphyria .
Acute intermittent porphyria (AIP)
One of the two most common types of the disease, FAT has no skin symptoms. The crises of this disease are intermittent, usually appear after puberty and its main symptoms are:
- Abdominal pain;
- Sickness;
- Vomiting;
- Constipation or diarrhea;
- Abdominal distension;
- Muscle weakness of the limbs;
- Change in sensitivity;
- Motor difficulties of cranial nerves.
After several severe attacks, it is possible that there is quadriplegia , which is when the patient loses the movements of all limbs.
Among psychiatric symptoms, there may also be hysteria, anxiety , apathy, depression , phobias, agitation, hallucinations, delirium, drowsiness or coma.
When the disease is treated, the attacks tend to disappear quickly, but without treatment it is dangerous and can lead to death.
Crisis triggers
If the patient has porphyria, the seizures can be caused or exacerbated by some factors. Are they:
Alcohol intake
In either type of porphyria, alcohol can exacerbate symptoms or cause seizures.
Excess iron
Especially in porphyria cutanea tarda, excess iron can worsen symptoms because it further inhibits the enzyme that causes this disease.
Contraceptives
Estrogen-based contraceptives can exacerbate crises of cutaneous porphyrias.
Infections
Infections are one of the main triggers of porphyria attacks of any kind. The hepatitis C virus , for example, can worsen skin symptoms. Severe infections can alter the body’s metabolism, triggering attacks of acute porphyria. Surgeries have the same effect.
HIV
HIV positive patients are more sensitive to the symptoms of cutaneous porphyria.
Tobacco
Cigarette causes acute attacks of porphyria and should be avoided to the maximum by patients with the disease.
Low calorie diet
Acute porphyrias can cause seizures when glucose is lacking in the patient’s body, and low calorie diets reduce the amount of this substance in the blood. Fasting has the same effect, which can lead to severe crises.
Medicines
There are many medications that can cause acute attacks of porphyria. Several of them are widely used. Sodium dipyrone (Novalgina, Lisador, Buscopan), dimenhydrinate (Dramin) and metoclopramide (Plasil) are some of them.
Many anticonvulsant medications can also cause seizures and should be avoided. It is important to note this, as one of the possible symptoms of seizures is seizures. Barbiturates also need to be avoided and, in the case of surgery, it is important that the anesthetist knows the condition.
Drugs
Several psychoactive drugs can serve as a trigger for acute porphyria attacks.
Halogenated hydrocarbons
Exposure to these substances can worsen the symptoms of cutaneous porphyrias. They are present in chloroform , in freon used in refrigeration and in certain pesticides. However, due to their toxicity in general (not just to porphyria patients), they are being replaced by other substances and contact with them is not common.
How is the diagnosis made?
There are a few ways to diagnose porphyria. It is important to note that in most cases the sample must be taken during a crisis, otherwise the result may be a false negative.
Bloodtests
During attacks of porphyria, there is a concentration of porphyrins (the precursors of heme) that can be detected by blood tests.
Urine and stool tests
In cases of acute porphyria , with the exception of ALAD porphyria, it is possible to find porphobilinogen (PBG) in the urine. Since porphyria is a rare disease, this is usually the sign that creates suspicion of its presence.
PGB causes the urine to turn a reddish color. This tone is accentuated when the urine is exposed to sunlight.
Spectroscopy
Spectroscopy is an examination that seeks to find certain chemicals in the tissue to be examined. A light is shone on the skin, urine or biopsy sample. Porphyrins, if present, will absorb and reflect specific spectra of light and through them it is possible to diagnose porphyria.
Genetic examination
If porphyria is suspected due to the presence of the disease in the family, genetic testing can be performed to find similar changes.
This test does not need to be performed during a crisis, but due to the wide variety of genetic changes that can lead to the disease, it is usually performed only when changes in the family are known.
Porphyria has a cure?
In general, porphyria has no cure . It is a genetic disease and cannot be cured, but treatment is possible to reduce the symptoms affecting the patient.
Liver transplantation can cure acute intermittent porphyria (AIP), however this treatment is only used in extremely severe cases of the disease, since a liver transplant is a very risky procedure . If the organ is rejected by the body, the patient can die.
Likewise, bone marrow transplantation can cure skin porphyrias, but the risks are far greater than the benefits.
What is the treatment?
The treatment of porphyria attacks is dependent on the type of porphyria.
Acute porphyria
The symptoms of acute porphyria are more severe than that of the skin and there is frequent hospitalization during PAI crises for the treatment of severe symptoms.
Carbohydrate-rich food
The main treatment for acute porphyrias is carbohydrate intake . The diet must be rich in carbohydrates so that there is glucose in the patient’s blood, since the lack of the substance is one of the main causes of the crises.
Administration of heme and glucose
When seizures are severe, heme is administered intravenously. Over the next few days, the body reduces the concentration of porphyrins that cause acute porphyria.
Glucose (both oral and intravenous) can be administered to patients in crisis, especially when the crisis is caused by caloric deficiency, however, heme is more efficient.
Medicines
Opioids can be prescribed to control pain caused by porphyria. Medication for nausea, vomiting and anxiety and insomnia may also be required .
The doctor should check that the patient is not taking any medication that could cause the seizures. The treatment of seizures can be especially complicated because almost all anticonvulsants aggravate porphyria attacks.
Liver transplant
In extremely severe cases of acute intermittent porphyria (AIP) , liver transplantation can be performed. It effectively cures the disorder, but it is accompanied by several serious risks, such as organ rejection and the need for immunosuppressive drugs for the rest of your life.
The transplant is only done in cases where there is a risk of permanent damage to the kidneys or the central nervous system of the patient and his quality of life is reduced. Some people may need a kidney transplant due to damage already done.
Porphyria cutanea
Unlike acute porphyrias, the cutaneous have a simpler and less suffered treatment.
It is necessary to avoid porphyria triggers. In addition, the following treatments can be used:
Phlebotomy
Phlebotomy is a procedure that involves removing a certain amount of blood from the body and is recommended in mild cases of porphyria cutanea tarda .
About half a liter of blood is drawn from the patient’s body through a needle. This reduces the amount of iron and porphyrins in the blood. 6 to 10 sessions are applied with intervals of 2 to 4 weeks per session.
Increased excretion of porphyrins
Using medications such as chloroquine and hydroxychloroquine in very low doses can help eliminate porphyrins from the urine.
Bone marrow transplant
Bone marrow transplantation has the potential to cure the disease, but that is not certain. As in the case of liver transplantation, this surgery can cause serious problems and lead to death due to the rejection of the bone marrow, in addition to the need to use immunosuppressive drugs for the rest of your life.
Splenectomy
Surgical removal of the spleen may be beneficial for patients suffering from hemolytic anemia caused by porphyria.
Solar protection
It is extremely important to protect your skin from the sun and other sources of ultraviolet light with clothing and sunscreen.
Medicines
Drug treatments for porphyrias are limited and not always effective. Some medications can be used to reduce the amount of specific porphyrins in the body, but the most frequent is that they are used for pain, since glucose is necessary to eliminate the most serious attacks of the disease.
Acute porphyria
Reduced heme production
- Hematin;
- Embanked de heme.
These two drugs reduce the activity of the enzyme ALA synthase, the first in the heme production line, and prevent the accumulation of porphyrins from continuing to increase.
Ache
- Morphine ( Dimorph );
- Tramadol(Tramal).
Since the pain caused by acute porphyrin attacks is extremely severe, opiate medications are indicated for its control. The substances are indicated to relieve the pain of crises, as well as neuropathic pain that can be caused by them.
Porphyria cutanea
- Chloroquine;
- Hydroxychloroquine.
These drugs reduce the amount of some porphyrins in the blood, eliminating them through the urine.
Attention!
NEVER self-medicate or stop using a medication without first consulting a doctor. Only he will be able to tell which medication, dosage and duration of treatment is the most suitable for his specific case. The information contained in this website is only intended to inform, not in any way intended to replace the guidance of a specialist or serve as a recommendation for any type of treatment. Always follow the instructions on the package insert and, if symptoms persist, seek medical or pharmaceutical advice.
Living together
The patient suffering from porphyria may have to deal with the disease for life. Monitoring by a multidisciplinary team may be necessary and very beneficial for the patient.
Multidisciplinary team
It may be necessary to monitor a team of doctors, psychologists, occupational therapists, nutritionists and dentists. Among medical specialties, it may be necessary to be accompanied by dermatologists, gastroenterologists, nephrologists, neurologists, hematologists, hepatologists, cardiologists, geneticists, among others.
Psychological treatment
Due to the depression that often accompanies cases of porphyria, psychological treatment is recommended for patients suffering from the disease.
Wear alert bracelet
Alert bracelets can be used so that, in cases of accidents that prevent the patient from communicating, doctors know about porphyria and avoid the use of medications that can cause crises.
Sunscreen
The use of sunscreen is extremely important for patients suffering from cutaneous porphyria. It is impossible to avoid the sun all the time, so protecting yourself is necessary.
Avoid triggers
Avoid drinking, smoking, using psychoactive drugs and having a protein diet to avoid attacks of porphyria.
Care for the disease is very necessary to guarantee a normal life. Avoiding the sun and other triggers, eating plenty of carbohydrates and visiting the doctor frequently are extremely important to live with porphyria.
Drugs that can cause acute porphyria attacks
This list contains drugs that can cause porphyria attacks. It is not because this medicine is here that it will necessarily cause the crisis, but the chances are high and that is why patients with the disease should avoid them as much as possible.
Due to the variety of types of porphyria, talking to your doctor is still essential to know which medications can and cannot be taken.
- Anesthetics: Lidocaine ;
- Anticonvulsants: Barbiturates, carbamazepine , ethosuximide, lamotrigine , phenytoin , sodium valproate ;
- Antihistamines: Clemastine , dimenhydrinate , hydroxyzine ;
- Hipoglicêmicos: Clorpropamida, glimepirida, glipizida, gliburida, tolbutamida;
- Antimicrobials: Chloramphenicol , clindamycin, erythromycin , ketoconazole , nitrofurantoin , rifampin, ritonavir , sulfonamides, trimethoprim;
- Cardiac Medications: Hydralazine , Lidocaine, Methyldopa , Nifedipine , Spironolactone ;
- Hormones: Danazol , estrogens, progesterone , synthetic progestins;
- Migraine medications: Dihydroergotamine;
- Sedatives: Barbiturates.
Prognosis
Acute porphyria attacks can be extremely painful, but treatment and care can reduce their number and ensure a more comfortable and better quality of life.
In the case of cutaneous porphyrias, the symptoms are milder, but almost constant. It is important to protect yourself from the sun, but it is possible to live well.
In both cases, a normal life is possible. Treatment must be followed in order to improve the quality of life.
Complications
Each type of porphyria has its complications. Understand:
Porphyria cutanea
If left untreated, porphyria cutanea can cause serious skin problems, blisters and ugly wounds, leave scars and facilitate the entry of bacteria into the body.
Over time, porphyria cutanea can lead to severe deformations in the facial appearance and the skin as a whole, in addition to the gums.
Acute porphyria
Without treatment, acute porphyria can cause serious physical and psychological damage. The pain is tremendous and the toxicity of the accumulation of heme precursors can cause:
Renal insufficiency
The accumulation of porphyrins can impair the kidneys’ ability to function.
Respiratory failure
Muscle weakness and paralysis can affect patients with porphyrias and this can lead to respiratory arrest.
Neurological problems
Porphyrins are toxic and, when they affect the central nervous system, can cause serious neurological problems.
Quadriplegia
Also due to the toxicity of porphyrins accumulating in the central nervous system, quadriplegia can be a consequence of repeated attacks of acute porphyria.
Hepatocarcinoma
Hepatocarcinoma is the most common type of liver cancer and can be caused by porphyrias.
Depression
Depression often accompanies critically ill patients and can lead to suicide.
How to prevent
Because it is a genetic disease, prevention of porphyria is not possible. However, couples can have a DNA test to see if they have the altered gene.
Genetic counseling is an option. The geneticist doctor will examine and explain any genetic alteration present in a couple who wish to have children, showing possible paths and options.
Common questions
These are some frequently asked questions about porphyria:
I have porphyria. What doctor should I look for?
It is likely that you will need a multidisciplinary team . It is composed of doctors, physiotherapists, psychologists, speech therapists, occupational therapists, among others. Each will have their role in the treatment. The general practitioner and family doctor can help guide you through the first steps. The symptoms that appear are that indicate which specialty you should look for.
Can I get porphyria?
No. None of the porphyrias can be transmitted from a sick person to a healthy one, they are all genetic. Even porphyria cutanea tarda, which may not be inherited, cannot be passed on to someone healthy and cannot be taken from someone. Porphyrias are not an infection.
Can I be retired due to disability?
Perhaps. The diagnosis of porphyria, by itself, cannot lead to retirement due to disability, but some cases of the disease can cause loss of muscle strength or neurological conditions with the risk of affecting the patient’s work capacity.
A medical consultation is necessary to find out if your specific condition can lead to disability retirement. A social worker can provide more information.
My doctor does not know the disease. What to do?
It is common for doctors not to know porphyria. It is a rare disease and the symptoms of which are quite common in other diseases. It is important that the doctor is informed about the condition. For this, he can contact the Brazilian Association of Porphyria .
Porphyrias are a set of genetic diseases that can cause serious skin, neurological and physical problems. The disease has no cure, but it is possible to live with it. Share this text with your friends so that they learn a little more about this rare disease!
