INTRODUCTION TO PORPHYRIA

The porphyrias are a group of rare inherited or acquired disorders of certain enzymes that normally participate in the production of porphyrins and heme. They manifest with either neurological complications or skin problems, or occasionally both.

Porphyrias are classified in two ways, by symptoms and by pathophysiology.

Symptoms: Are normally acute porphyrias present within the nervous system, resulting in severe abdominal pain, vomiting, neuropathy and mental disorders. Another form of symptomatic porphyria is cutaneous porphyrias which present in skin manifestations after exposure to sunlight. 

Pathophysiology: Further classified into erythropoietic or hepatic based on areas of accumulation of heme precursors, either in liver, bone marrow or red blood cells. 

BIOCHEMISTRY BEHIND THE DISEASE

The Haem Synthetic Pathway

Porphyria arises from defects in the biosynthetic pathway leading to the production of haem (haem synthetic pathway). In this pathway, glycine and succinyl-CoA combine to form the first porphyrin precursor, aminolaevulinic acid (ALA); two molecules of ALA then combine to form the second porphyrin precursor porphobilinogen (PBG), and four molecules of PBG combine to form uroporphyrinogen. Uroporphyrinogen is the first true porphyrin, showing the characteristic tetrapyrrole configuration of a porphyrin. Uroporphyrinogen then undergoes a systematic rearrangement of its hydrocarbon side chains, resulting in a series of different porphyrinogens.

Fig. 1.1: Protoporphyrin- insertion of iron atom results in haem compound

(In tetrapyrrole configuration)

Porphyrins and Porphyrinogens

The tetrapyrroles exist in two forms: a reduced form known as the porphyrinogens and an oxidised form known as the porphyrins. The porphyrinogens (uroporphyrinogen, coproporphyrinogen etc.) constitute the intermediates on the haem synthetic pathway, but tend to become oxidised when they escape from this pathway into blood, urine and stool: it is therefore the porphyrins which are measured in the laboratory.

Enymes of the Haem Synthetic Pathway Each step in this pathway is catalysed by an enzyme. Where an enzyme is deficient, the porphyrins or their precursors accumulate, resulting in one or other of the diseases collectively known as the porphyrias.

Haem is required in erythroid tissue for the production of hemoglobin, as well as in non-erythroid tissues (tissue in liver), where it is incorporated into many haemoproteins, including the cytochromes. This allows a division of the porphyrias into two major categories: the erythropoietic porphyrias, in which the enzyme defect manifests in the haem synthetic pathway within erythroblasts, resulting in the accumulation of porphyrin within red blood cells, and the non-erythropoietic or hepatic porphyrias, in which porphyrins are overproduced in the liver.

Fig. 1.2: The Haem Synthetic Pathway

Contracting the Disease

In most cases the defective enzyme is caused by a mutation in the gene coding for that enzyme. Most porphyrias are therefore genetic disorders, and may be transmitted as autosomal dominant or recessive conditions. An important exception is porphyria cutanea tarda (PCT), which is usually an acquired, rather than an inherited, disorder.

Fig. 1.3: A patient with congenital erythropoietic porphyria. 

Extensive excoriation, ulceration, and scarring in the face with severe cartilage destruction on the nose resulting in mutilation. Eyebrows and eye-lashes are lost.

 

1      1. What causes porphyria?

Porphyria is a rare disorder passed down through families, in which an important part of haemoglobin, called heme, is not made properly.

The body made heme in multiple steps, each step is controlled by a particular enzyme. However, for patient with porphyria, there is a deficiency of this enzyme, so the process is blocked and porphyrins and their precursors accumulate in a toxic level in the patient’s body.

2. How does porphyria affect the patients?

Patients with porphyria will feel abdominal pain or cramping. When they are exposing to light, rashes appear. And they would experience blistering and scarring of the skin as well. Their nervous system and muscles would be affected at the same time. They will have problems such as seizures, mental disturbance and nerve damage. Porphyria patients would vomit and constipate when they are not feeling well. A physical damage caused by porphyria is scarring of the hair follicles which can cause irritation.

 Fig. 1.4 Cross-section of a strain of hair

(scarring observed)

3.What are the treatments for porphyria?

There isn’t a cure for porphyria yet, however, medicines were used to treat a sudden attack of porphyria.  Patients were given sedatives and chloroquine. They would consume propranolol to control the heartbeat or they could have hematin injected through their vein. And to increase their blood glucose level, fluids and glucose will be injected into them as well. Another treatment for a sudden attack of porphyria could be the removal of blood. The patients could have beta-carotene supplements to control the condition of their illness.

4. Can porphyria be prevented?

As porphyria is hereditary, people who have a family history of any type of porphyria and want to have children can go for genetic counseling. A genetic counselor would review your family history and suggest appropriate testing for you, at the same time assess the risk of your offspring contracting this disorder.

Although such gene mutation can yet be corrected, porphyria attacks can be anticipated and thus, prevented depending on which type of porphyria the patient suffers from.

For example, a patient with Acute Intermittent Porphyria can prevent attacks by avoiding triggers such as alcohol, certain drugs, stress or even weight loss (dieting). On the other hand, sufferers of Congenital Erythropoietic Protoporphyria should avoid sunlight. In general, by avoiding triggers that causes porphyria attacks, porphyria patients are able to minimize number of attacks and strive to have the best quality of life.