Porphyria

Ira Shah
Consultant Pediatrician, B.J.Wadia Hospital for Children, Mumbai, India
First Created: 02/28/2001 

Introduction

Porphyrias are a heterogeneous group of either inherited or acquired disorders of heme biosynthesis which cause either skin problems or a condition known as an acute attack.

Porphyrias are a rare disorder. They occur due to the specific abnormality of various enzymes in the biosynthetic pathway of heme production. As a result, excess amounts of porphyrias and their precursors accumulate in the body causing generalized clinical abnormalities.

Types of Porphyria

Porphyrias can be classified into two groups depending on whether they cause acute or non-acute symptoms.

Acute porphyrias

: Consists of the following conditions:
  • Acute Intermittent Porphyria (AIP)(Swedish porphyria): It is due to a decrease in porphobilinogen deaminase.

  • Variegate Porphyria (VP) (South African Genetic porphyria): In addition to the acute attack, it may also cause skin problems. It is caused by a decrease in protoporphyrinogen oxidase.

  • Hereditary Coproporphyria (HCP) (Coproporphyria): It also causes skin disorders. It is caused by a decrease in coproporphyrinogen.

  • Plumboporphyria (PP)(ALA dehydratase deficiency): It is a very rare disorder and is similar to AIP.

    All acute porphyrias are inherited as autosomal dominant conditions.

Non-acute porphyria

: It consists of

  • Porphyria Cutanea Tarda (PCT) (Cutaneous Hepatic Porphyria: Symptomatic Porphyria): It is usually an acquired disorder and is precipitated by alcohol, drugs, or exposure to certain chemicals. It may also develop in people with kidney failure on hemodialysis. Skin problems are a common presentation in these patients.

  • Erythropoietic Protoporphyria (EPP): It is an autosomal dominant condition. Patients with EPP suffer from skin problems and the liver may become involved in later years.

  • Congenital Porphyria(Gunther's disease) (CP): It is the rarest of all the porphyrias and causes skin problems. It is the only porphyria, which is inherited as a recessive condition.

Presentation

Acute porphyrias vary in their clinical presentation. During an attack, the affected patient may suffer from abdominal pain, cramps, constipation, nausea, or vomiting. Also, they may have altered behavior. Severe cases may have weakness and paralysis due to peripheral neuropathy. There may be autonomic dysfunctions like tachycardia, hypertension, postural hypertension, profuse sweating, pallor, and pyrexia. Severe hyponatremia may be present due to SIADH, which may cause convulsions.

In patients with VP and HCP, there may also be additional skin involvement and solar photosensitivity.

How Do Acute Attacks Occur?

Most of the patients who inherit the disorder enjoy normal health, However, they are at risk of developing an attack if exposed to various precipitating factors such as alcohol, infection, dieting, and drugs. Pregnancy and oral contraceptives may also precipitate attacks. Some women may experience a regular attack, one week premenstrual.

The drugs commonly causing the acute attack are:

  • Diuretics like frusemide, hydrochlorothiazide

  • Antihypertensives like Alpha Methyl Dopa, Enalapril, Hydralazine, Lisinopril, Nifedipine, Verapamil

  • Antihistamines like Dimenhydrinate, Terfenadine.

  • Hypnotics like Amylobarbitone, Diazepam, Flurazepam.

  • Anticonvulsants like Barbiturates, carbamazepine, ethosuximide, Hydantoins, Phenytoin.

  • Antibiotics: Chloramphenicol, Erythromycin, Cloxacillin, Griseofulvin, Pyrazinamide, Sulphonamides.

  • Miscellaneous-Oral contraceptives, Sulphonylureas, Ergotamine.

Skin Problems In Porphyria

Skin problems in porphyria are usually acquired conditions. Patients with VP, HC, CP, and PCT have very sensitive skin, which is easily damaged. Sunlight often causes the skin to become fragile particularly in those areas exposed to light like hands, faces, neck, legs, and feet. Their skin develops blisters and sores. Long term, their skin becomes thin, dark, scarred, and often hairy. EPP and CP present at a much younger age and have severe symptoms.

Investigations

Testing A Family Member:
Since acute porphyrias are autosomal dominant conditions, there is a 50% chance that the child may be affected if one of the parents has the disease. However, the disease may remain latent for a prolonged time. Latent cases can be diagnosed by measuring porphyrins and their precursors in urine, feces, and blood, or measuring the various enzymes of the heme biosynthetic pathway. Young children may not show signs of their porphyria till puberty and laboratory tests may not even pick it up till then. Hence, it is safer to have children follow the same precautions to minimize the risk. These children should be tested every two years from the age of 12 until they are 20 years old. If the tests are still negative, it is unlikely that the child may suffer from porphyria. However, the child may still have the defective gene, hence it is wise that no member of a porphyric family should take such drugs until essential.

Diagnosis

Any patient presenting with unexplained abdominal pain, mental dysfunction, or peripheral neuropathy should be suspected to have acute porphyria. A clue to the diagnosis is the dark reddish-brown color of the urine during an attack, which becomes more pronounced if it is left standing. A simple urine test can be done to test for the presence of porphobilinogen in the urine. Either 200 ml of 24-hour urine is tested (with no added preservative) or a spot sample of at least 100 ml urine can be tested. Equal volumes of urine and Ehrlich's reagent are mixed in a tube. If the solution becomes pink, it indicates either the presence of porphobilinogen or urobilinogen. The presence of porphobilinogen can be confirmed by the addition of about two volumes of chloroform to the solution and completely shaking it. The mixture is allowed to stand. If the pink color remains in the upper aqueous layer, it shows the presence of porphobilinogen. If it moves to the lower layer, it denotes the presence of urobilinogen.

Treatment of Acute Attack

Treatment consists of both supportive and specific therapy. Any patient in an acute attack requires symptomatic treatment for the following conditions:

Pain: When mild, it can be controlled with aspirin, paracetamol, or dihydrocodeine. For severe pain, pethidine or morphine may be required. Sleep diminishes pain, hence chlorpromazine with analgesics may be useful. Patients should be left undisturbed in a darkened room.

Nausea, vomiting, and constipation: They can be controlled with chlorpromazine, prochlorperazine. If constipation is severe enough to cause obstipation, neostigmine may be useful.

Tachycardia & Hypertension: They are due to sympathetic overactivity and can be controlled by propranolol. If there is evidence of cardiovascular instability, continuous cardiac monitoring is required.

Convulsions: Hyponatremia should be corrected by restricting fluid intake. It could also be a sign of hypertensive encephalopathy and blood pressure should be corrected. Convulsions are usually present only during an attack and remit as the symptoms resolve.

Peripheral neuropathy: Watch should be kept for respiratory fatigue. The expiratory peak flow rate should be monitored. If there is any decrease in this rate, the blood gases should be checked and the patient should be in ICU with facilities for assisted ventilation. Proper physiotherapy should be maintained in a paralyzed patient.

Specific therapy consists of:
Hematin therapy: Hematin is the end product of the heme pathway. Thus, it acts by supplementing the depleted heme pool and repressing the activity of the initial enzymes of heme biosynthesis, thus reducing the overproduction of porphyrins. In the acute attack, it is given intravenously. There are no major side effects except for phlebitis around the injection site. This can be prevented by giving hematin with human albumin solution to which it will bind. It may also cause prolongation of prothrombin and partial thromboplastin times, which revert to normal on stopping the drug. In patients with renal failure, the dose of drugs should be reduced.

High Carbohydrate Intake: Most patients have nausea and vomiting in the attack and their poor carbohydrate intake further aggravates the disease. Hence, glucose should be supplemented either orally or intravenously.

Prevention of An Acute Attack

By maintaining a regular diet, avoiding alcohol and certain drugs, most of the attacks can be prevented. For patients who have attacks premenstrually, prophylactic LHRH analogs can be tried long term. Patients who have acute attacks should avoid pregnancy until they are free of symptomatic attacks for at least 18 months as pregnancy may precipitation an acute attack.

To avoid the photosensitivity seen in VP and HCP, Beta-Carotene treatment may be useful.

Prevention of Skin Problems

The best way to treat the skin condition is to prevent it. Avoiding sunlight is the most beneficial therapy. Sun-exposed areas can be protected by wearing long sleeves, gloves, and a hat. The patient should go out only in the early morning or late afternoon. Sunscreens, which can help, are opaque zinc or titanium oxide, however, they are thick and greasy.

Non-acute Porphyria

There is no cure for porphyria. However, it can be made less severe. Patients with PCT should avoid alcohol. If skin conditions remain bad, venesection is indicated. This removes about 10 cc\kg\body weight of the patient's blood at regular intervals usually fortnightly for about eight weeks. Patients with EPP should be regularly tested for liver dysfunction.


Porphyria Porphyria Porphyria 02/28/2001
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