Learn about the symptoms, types, and management of porphyria, a group of rare genetic disorders. Get valuable insights at Meri Sehat.

Porphyria

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Saad Ullah Siddiqui

Overview

Porphyria is the umbrella term for rare genetic disorders that affect the production of heme, a component of hemoglobin. 
Porphyria is a group of genetic disorders that affect the body&#39;s ability to produce heme, a chemical that is an essential component of several enzymes and molecules that interact with oxygen. 
&nbsp;

The name &quot;porphyria&quot; comes from the Greek word &quot;porphyrus,&quot; meaning purple, as some patients with porphyria excrete reddish-purple urine due to the presence of excess porphyrins. Additionally, their urine darkens when exposed to light.

Heme is produced in the bone marrow and liver through a series of eight steps, with a specific enzyme responsible for each step. When there is an abnormality in the pathway for making heme, some of the intermediary enzymes accumulate and cause symptoms of porphyria.

These intermediates are either porphyrins or porphyrin precursors, and the effects on the body depend on which intermediates are building up. If porphyrin precursors accumulate, they have negative effects on the nervous system, while an excess of porphyrins cause sensitivity to light and skin photosensitivity. 
&nbsp;

The prevalence of porphyria is uncertain, but it&#39;s estimated that around 1 in 20,000 individuals have some form of the condition1. Certain types of porphyria are more prevalent in certain populations. For instance, acute intermittent porphyria is more prevalent in Sweden compared to other regions, while porphyria cutanea tarda is the most widespread form, affecting approximately 1 in every 25,000 people in the United States<a href="#accordion">[1]</a>.

Moreover, erythropoietic porphyria is the most common among children, with the highest frequency observed in the Netherlands at a rate of around 1 in 75,000 individuals<a href="#accordion">[1]</a>.

Based on European studies, congenital erythropoietic porphyria is extremely rare, having an incidence of 1 in 1,000,000 or fewer. Also, there are only 9 recorded cases of ALAD-deficiency Porphyria<a href="#accordion">[2]</a>. 
&nbsp;

Porphyria can be classified based on the symptoms<a href="#accordion">[2][3]</a>. 
&nbsp;

<h5>Acute Porphyria:</h5>

Acute porphyria is a group of illnesses that frequently result in nervous system issues, manifesting suddenly and with intense severity. These symptoms persist for a few days to several weeks, but typically improve gradually following the onset of episode<a href="#accordion">[4]</a>. 
&nbsp;

<ul>
	<li>Acute Intermittent Porphyria: It is an uncommon metabolic disorder caused by a partial lack of the enzyme hydroxymethylbilane synthase (also known as porphobilinogen deaminase). This shortage of the enzyme can lead to the buildup of porphyrin precursors in the body.</li>
	<li>Delta-Aminolevulinic Acid Dehydratase (ALAD) Porphyria: This kind of porphyria results from a severe deficiency of ALAD, which is caused by a genetic defect. It is often referred to as Doss porphyria. It is the least common of the inherited porphyrias, with only 8 known cases reported globally and all occurring in males<a href="#accordion">[5]</a>. 
	&nbsp;</li>
</ul>

<h5>The Cutaneous Porphyria:</h5>

Cutaneous porphyrias are variants of the condition that induce skin symptoms as a result of sensitivity to sunlight, but they rarely impact the nervous system<a href="#accordion">[4]</a>. 
&nbsp;

<ul>
	<li>Porphyria Cutanea Tarda (PCT): PCT manifests as painful and blistering skin lesions due to photosensitivity. Exposure to sun and a lack of the enzyme uroporphyrinogen decarboxylase causes it<a href="#accordion">[6]</a>. 
	&nbsp;</li>
	<li>Hepatoerythropoietic Porphyria (HEP): HEP is caused by a lack of the enzyme uroporphyrinogen decarboxylase. 
	&nbsp;</li>
	<li>Congenital Erythropoietic Porphyria (CEP): CEP is a metabolic condition that typically presents in early childhood. It is caused by a deficiency in the enzyme uroporphyrinogen ll co-synthase, the fourth enzyme in the heme biosynthesis pathway. 
	&nbsp;</li>
	<li>Erythropoietic Protoporphyria (EPP): EPP is caused by a hereditary lack of the enzyme ferrochelatase activity. It causes a buildup of protoporphyrins in red blood cells. 
	&nbsp;</li>
	<li>X-linked Protoporphyria (XLP): XLP is caused by a hereditary increase in delta-aminolevulinic acid synthase-2 activity. 
	&nbsp;</li>
</ul>

<h5>Neurocutaneous Porphyria:</h5>

This condition affects both the skin and the nervous system. Sunlight exposure tends to rapidly trigger symptoms. 
&nbsp;

<ul>
	<li>Hereditary Coproporphyria: HCP is a metabolic condition caused by a lack of coproporphyrinogen oxidase.</li>
	<li>Variegate Porphyria: Variegate porphyria is defined by a protoporphyrinogen oxidase enzyme deficiency. 
	&nbsp;</li>
</ul>

Signs and Symptoms

Porphyria symptoms can vary greatly in severity, type, and person. Some people who have the gene abnormalities that produce porphyria exhibit no symptoms. 
&nbsp;

Acute Porphyria - It is characterized by abdominal pain and neurological symptoms that develop over a period of several days. It can also affect the skin after sun exposure. The following are the symptoms of acute porphyria:

<ul>
	<li>Severe abdominal pain</li>
	<li>Pain in the chest, legs, or back</li>
	<li><a href="https://merisehat.pk/disease/constipation">Constipation </a>or <a href="https://merisehat.pk/disease/diarrhea">diarrhea</a></li>
	<li>Nausea and vomiting</li>
	<li>Muscle pain, tingling, numbness, weakness, or paralysis</li>
	<li>Mental changes, such as <a href="https://merisehat.pk/disease/anxiety">anxiety</a>, confusion, hallucinations, disorientation, or paranoia</li>
	<li>Breathing problems</li>
	<li>Urination problems</li>
	<li>Rapid or irregular heartbeats</li>
	<li><a href="https://merisehat.pk/disease/hypertension-57">High blood pressure</a></li>
	<li>Seizures 
	&nbsp;</li>
</ul>

Cutaneous Porphyria &ndash; People suffering from cutaneous porphyria, which generally affects the skin on hands, forearms, ears, and neck, frequently encounter the following symptoms:

<ul>
	<li>Oversensitivity to sunlight</li>
	<li>Itching</li>
	<li>Swelling of skin exposed to sunlight</li>
	<li>Abrasions, blisters, and skin erosions</li>
	<li>Scarring leading to fragile skin</li>
	<li>More hair growth</li>
	<li>Darkening and thickening of the skin 
	&nbsp;</li>
</ul>

Causes

The different forms of porphyria result from a lack of specific enzymes needed for producing heme. Heme is a crucial pigment; it contains iron, which is essential for the proper functioning of blood and liver. Hemoglobin in the blood uses heme to carry oxygen to tissues and gives red blood cells their red color, while proteins in the liver use heme to help them work correctly.

The production of heme involves several stages and along the way, other substances called porphyrins and porphyrin precursors are generated. If there is a shortage of any of the enzymes necessary for heme production, these porphyrins and precursors accumulate and cause symptoms of one of the porphyria forms. 
&nbsp;

<ul>
	<li>Genetic Forms: The majority of porphyria is hereditary. It can exhibit one of the following patterns: 
	&nbsp;</li>
</ul>

Autosomal Dominant Pattern - Condition occurs when a variant is present in only one allele of a given gene.

Autosomal Recessive Pattern - The child inherits one mutated copy of a gene from each parent. The parents usually do not have the condition and are hence called carriers because they each carry one copy of the mutated gene and can pass it to their children.

However, inheriting a defective gene or genes does not guarantee that the individual will present with its symptoms. An individual can have latent porphyria and never experience symptoms. This is true for the vast majority of carriers of defective genes. 
&nbsp;

<ul>
	<li>Acquired Forms: PCT is commonly acquired rather than inherited. Certain factors that influence enzyme synthetase, such as an excess of iron in the body, liver disease, estrogen prescription, smoking, or excessive alcohol consumption, can produce symptoms. 
	&nbsp;</li>
</ul>

Diagnosis

Porphyria can be difficult to diagnose because the symptoms are similar to those of other disorders. If the doctor suspects it, they may request blood, urine, and stool tests to confirm the diagnosis.

Since porphyria typically runs in families, the doctor may also recommend genetic testing. 
&nbsp;

Treatment

The treatment of porphyria depends on the type and severity of the condition, as well as the individual&#39;s specific symptoms and overall health. Hepatic disease treatments include<a href="#accordion">[10]</a>:

<ul>
	<li>Beta-blockers, such as atenolol, to control blood pressure</li>
	<li>A diet strong in carbohydrates</li>
	<li>Opioids for pain relief</li>
	<li>Hematin to shorten attacks</li>
	<li>Gene therapies, such as givosiran 
	&nbsp;</li>
</ul>

Please Note: Givosiran was authorized by the Food and Drug Administration for treating adults with acute hepatic porphyria. 
&nbsp;

Erythropoietic disease treatments include:

<ul>
	<li>Anemia iron supplements</li>
	<li>Blood transfusions</li>
	<li>Bone marrow transplant 
	&nbsp;</li>
</ul>

It is important to note that treatment for porphyria may need to be adjusted over time as the condition changes and that individualized treatment plans are best developed in consultation with a physician who is knowledgeable about porphyria. 
&nbsp;

Complications may be possible depending on the type of porphyria: 
&nbsp;

<h5>Acute Porphyria</h5>

Acute porphyria is potentially fatal. Possible complications include:

<ul>
	<li><a href="https://merisehat.pk/disease/dehydration">Dehydration</a></li>
	<li>Breathing difficulties</li>
	<li>Seizures</li>
	<li>High blood pressure</li>
	<li>Chronic discomfort</li>
	<li><a href="https://merisehat.pk/disease/chronic-kidney-disease">Chronic kidney disease</a></li>
	<li>Liver damage 
	&nbsp;</li>
</ul>

<h5>Cutaneous Porphyria</h5>

Cutaneous porphyria may result in long-term skin damage. It may have complications, such as:

<ul>
	<li>Infected blisters</li>
	<li>Discoloration</li>
	<li>Fragile skin</li>
	<li>Scars 
	&nbsp;</li>
</ul>

Environmental variables, in addition to genetic risk factors, may contribute to the development of porphyria:

<ul>
	<li>Direct sunlight exposure</li>
	<li>Certain medications, including hormone drugs</li>
	<li>Recreational drugs</li>
	<li>Fasting or dieting</li>
	<li>Smoking</li>
	<li>Infections or other ailments that cause physical stress</li>
	<li>Emotional tension</li>
	<li>Alcohol</li>
	<li>Menstrual hormones cause acute porphyria attacks in girls before puberty and in women after menopause. 
	&nbsp;</li>
</ul>

The following steps can help prevent attacks of porphyria:

<ul>
	<li>Avoid Triggers: Identify and avoid any triggers that seem to bring on an attack, such as fasting, alcohol, stress, hormonal changes, or exposure to certain chemicals or drugs. 
	&nbsp;</li>
	<li>Maintain A&nbsp;Balanced Diet: Eating regular meals and avoiding fasting can help prevent symptoms. Make sure to include complex carbohydrates, protein, and healthy fats in your diet. 
	&nbsp;</li>
	<li>Manage Stress: Stress management techniques, such as relaxation therapy, exercise, and counseling, can help reduce the likelihood of an attack. 
	&nbsp;</li>
	<li>Avoid Exposure To Toxic Substances: Certain chemicals and toxins can trigger porphyria symptoms. Avoid exposure to these substances and wear protective clothing when necessary. 
	&nbsp;</li>
</ul>

Key Points

<ul>
	<li>Porphyria is a group of genetic disorders that affect the body&#39;s ability to produce heme, a chemical that is an essential component of several enzymes and molecules that interact with oxygen.</li>
	<li>If porphyrin precursors accumulate, they have negative effects on the nervous system, while an excess of porphyrins cause sensitivity to light and skin photosensitivity.</li>
	<li>The prevalence of porphyria is uncertain, but it&#39;s estimated that around 1 in 20,000 individuals have some form of the condition.</li>
	<li>Acute porphyria is a group of illnesses that frequently result in nervous system issues, manifesting suddenly and with intense severity. These symptoms persist for a few days to several weeks, but typically improve gradually following the onset of the episode.</li>
	<li>Cutaneous porphyrias are variants of the condition that induce skin symptoms as a result of solar sensitivity, but they rarely impact the nervous system.</li>
	<li>Porphyria symptoms can vary greatly in severity, type, and person. Some people who have the gene abnormalities that produce porphyria exhibit no symptoms. 
	&nbsp;</li>
</ul>

[1] Porphyrias. National Organization for Rare Disorders.

[2] About porphyria. American Porphyria Foundation.

[3] Department of Health & Human Services. Porphyria. Better Health Channel.

[4] Porphyria. Mayo Clinic.

[5] Porphyria. UpToDate.

[6] Porphyria Cutanea tarda. National Organization for Rare Disorders.

[7] Porphyria: Symptoms, causes, treatments. Cleveland Clinic.

[8] Porphyria: Types, symptoms, causes, and treatment. WebMD.

[9] Porphyria: Medlineplus genetics. MedlinePlus.

[10] Krause L. Porphyria: Types, symptoms, and treatment. Healthline.

[11] Poli A, Schmitt C, Moulouel B, et al. Givosiran in acute intermittent porphyria: A personalized medicine approach. Molecular Genetics and Metabolism. 2022;135(3):206-214. doi:10.1016/j.ymgme.2022.01.002