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THE PORPHYRIAS

Porphyrias are a group of diseases that result from defective enzymes of heme biosynthesis. The seven different porphyrias correspond to an abnormality of a specific enzyme of the heme biosynthesis pathway. The genes coding for the enzymes are known in all porphyrias, and several mutations have been identified in porphyric patients.

Two major types of clinical manifestations occur in porphyrias. Acute porphyric attack, which is characterized by abdominal pain and neurologic manifestations, is a feature in acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria. In all three conditions the porphyrin precursors porphobilinogen and 5-aminolevulinic acid are accumulated during attacks. In other porphyrias cutaneous symptoms.

In symptomatic patients the specific porphyria can easily be diagnosed by specific laboratory tests. Most porphyrias are inherited in autosomal dominant fashion, but the penetrance of the disease varies greatly. In many porphyrias, the majority of patients remain asymptomatic throughout their lives. Biochemical tests are often inaccurate in the diagnosis of latent cases of porphyria. When the underlying mutation in an affected family is known, the DNA diagnosis is accurate, but the genetic heterogeneity of individual porphyrias restricts usefulness of this method.

ACUTE PORPHYRIAS

The acute porphyrias--acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria-- are characterized by episodic acute attacks. During an acute attack, symptoms include severe abdominal pain, vomiting, constipation, often pain in the extremities and in the back, and psychologic symptoms that range from anxiety to delirium. Urine may be dark or red in color because of increased amounts of porphobilin and porphyrins. Sometimes the disease progresses to peripheral motor neuropathy.

Treatment of the Acute Attack

Treatment of acute porphyric attacks includes three different approaches: elimination of precipitating factors, specific therapy.

Elimination of Precipitating Factors

Acute porphyric attacks are often precipitated by factors such as certain drugs, excessive alcohol consumption.

Characteristics of Individual Porphyrias

Porphyria Main Clinical Symptoms Main Biochemical Tests

Acute intermittent porphyria Acute attacks Urinary porphobilinogen and5-aminolevulinic acid, erythrocyte porphobilinogen deaminase

Variegate porphyria (porphyria variegata) Acute attacks and skin fragility Fecal protoporphyrin, plasma fluorescence

Hereditary coproporphyria Acute attacks and skin fragility Fecal and urinary coproporphyrin

Porphyria cutanea tarda Skin fragility an liver disease Urinary uroporphyrin, plasma fluorescence

Erythropoietic protoporphyria Photosensitivity, liver damage Erythrocyte protoporphyrin, plasma fluorescence

Congenital erythropoietic porphyria Severe skin symptoms, hemolysis Urinary and erythrocyte uroporphyrin I

**Characteristics of Individual Porphyrias**
Porphyria	Main Clinical Symptoms	Main Biochemical Tests
Acute intermittent porphyria	Acute attacks	Urinary porphobilinogen and5-aminolevulinic acid, erythrocyte porphobilinogen deaminase
Variegate porphyria (porphyria variegata)	Acute attacks and skin fragility	Fecal protoporphyrin, plasma fluorescence
Hereditary coproporphyria	Acute attacks and skin fragility	Fecal and urinary coproporphyrin
Porphyria cutanea tarda	Skin fragility an liver disease	Urinary uroporphyrin, plasma fluorescence
Erythropoietic protoporphyria	Photosensitivity, liver damage	Erythrocyte protoporphyrin, plasma fluorescence
Congenital erythropoietic porphyria	Severe skin symptoms, hemolysis	Urinary and erythrocyte uroporphyrin I

Specific Therapy

Heme therapy and carbohydrate loading are specific therapies for acute porphyric attacks because these agents are able to reduce the overproduction of excess amounts of porphyrin precursors. Heme is much more effective in this regard.

Specific treatment is justified only when a patient has symptoms and signs compatible with an acute attack and increased excretion of porphobilinogen in the urine. The presence of symptoms without raised levels of porphobilinogen, or the finding of raised levels of porphobilinogen, 5-aminolevulinic acid, or porphyrins without symptoms.

Symptomatic Therapy

Patients with acute attacks usually have symptoms that may necessitate medication or other therapies. Pain is typically severe, often requiring opiate analgesics for control; morphine, meperidine, or other opiates in normal doses.

Seizures, which may occur during acute attacks, should not be treated with phenytoin or barbiturates because they are porphyric attack-precipitating drugs. Diazepam (Valium) and clonazepam (Klonopin) are probably safe and can be used in appropriate doses. Peripheral motor neuropathy tends to resolve slowly.

Prevention of Acute Attacks

After an acute attack the patient must be informed about precipitating factors to prevent future episodes. A list of unsafe drugs should be provided, and avoidance of alcohol consumption should be emphasized. Some authors recommend more strict regulation of dietary intake, e.g., a carbohydrate intake of 55 to 60% of total energy intake.

A few female patients with acute porphyria may have frequent symptoms associated with menstrual cycles. The symptoms usually develop during the premenstrual phase. Various hormonal manipulations have been tried for prevention of symptoms. Exogenous estrogens and progestins, e.g., oral contraceptive pills, have been reported to prevent attacks in some patients. These agents must be administered with caution, because female sex hormones are also regarded as precipitating drugs.

Management of acute attacks does not require identification of the exact type of acute porphyria, because the treatment and prevention are the same in all three types of acute porphyria. Prevention of attacks also includes evaluation of family members to find asymptomatic individuals with porphyria. In the asymptomatic phase, each of the acute porphyrias (acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria).

PORPHYRIA CUTANEA TARDA

Porphyria cutanea porphyria is the most common type of porphyria in the United States and Europe. Onset is usually during the fourth or fifth decade of life, and the disorder is manifested mainly as cutaneous symptoms and hepatopathy. Characteristic skin lesions are blistering and erosions on sun-exposed areas, mainly on the backs of the hands. Porphyria cutanea tarda is usually associated with chronic liver disease. Many patients consume excessive amounts of alcohol, and there is a high prevalence of hepatitis C.

Treatment

Predisposing factors such as alcohol, iron supplements, and estrogen preparations should be eliminated. In some cases this may result in clinical and biochemical remission.

Two specific and effective treatments for porphyria cutanea tarda are known, namely, iron removal by phlebotomy and low-dose chloroquine therapy. There is no general agreement on which is preferable; the use of chloroquine is more frequent in many European countries than in the United States, where chloroquine is recommended.

In phlebotomy, 400 to 500 mL of blood is removed at weekly or biweekly intervals until the blood hemoglobin concentration falls to 100 to 110 grams per liter. Usually, 4 to 10 liters of blood must be removed before therapeutic effects are seen. Measurement of urinary excretion of uroporphyrin or total porphyrins is useful for monitoring.

In low-dose chloroquine therapy, chloroquine (Aralen) or hydroxychloroquine (Plaquenil) is administered orally 125 mg twice a week. After remission induced by phlebotomy or chloroquine, a relapse usually occurs within 1 to 2 years. Clinical relapse can be predicted by monitoring urinary excretion of

ERYTHROPOIETIC PROTOPORPHYRIA

Erythropoietic protoporphyria is manifested as acute photoreactivity of the skin in childhood. Typical symptoms are stinging pain or itching with subsequent swelling.

RARE TYPES OF PORPHYRIAS

5-Aminolevulinic acid (ALA) dehydratase defect porphyria is a very rare type of porphyria that is caused by severe deficiency of 5-aminolevulinic acid dehydratase, the second enzyme of the heme biosynthetic pathway. It is inherited in autosomal recessive fashion, and fewer than 10 cases have been reported. The disease manifests itself in childhood and is usually associated with severe neurologic abnormalities suggestive of acute porphyric attacks. Heme therapy or liver transplantation.

Porphyrias that are inherited in autosomal dominant fashion and thus are manifested in the heterozygous state may rarely occur in homozygous forms. Homozygous cases of variegate porphyria and hereditary coproporphyria have been described. Onset is in childhood, with presenting manifestations of severe photosensitivity and nonspecific neurologic symptoms.

Hepatoerythropoietic porphyria is a homozygous form of porphyria cutanea tarda. The disease manifests itself in early childhood with severe skin problems that may lead to scarring and mutilation as in congenital erythropoietic porphyria.