Section 12. Disorders of Nutrition and Metabolism

Chapter 160. Porphyrias

Topics: Introduction | Porphyria Cutanea Tarda | Acute Intermittent Porphyria | Erythropoietic Protoporphyria

Acute Intermittent Porphyria

Acute intermittent porphyria, which causes neurologic symptoms, is the most common acute porphyria.

Acute intermittent porphyria occurs in people of all races but may be more common in those from Northern Europe. In most countries, it is the most common of the acute porphyrias. People first experience acute intermittent porphyria with acute onset of neurologic symptoms. Attacks are more common in women than in men.

Acute intermittent porphyria is due to a deficiency of the enzyme porphobilinogen deaminase (also known as hydroxymethylbilane synthase) that leads to accumulation of the heme precursors delta-aminolevulinic acid and porphobilinogen initially in the liver. The disorder is inherited due to a single abnormal gene from one parent. The normal gene from the other parent keeps the deficient enzyme at half-normal levels, which is sufficient to produce normal amounts of heme. Very rarely, the disease is inherited from both parents (and therefore two abnormal genes are present); symptoms may then appear in childhood and include developmental abnormalities.

Most people with a deficiency of porphobilinogen deaminase never develop symptoms. In some people, however, certain factors--drugs, hormones, or diet--can precipitate symptoms, producing an attack. Many drugs (including barbiturates, anticonvulsants, and sulfonamide antibiotics) can bring on an attack. Hormones, such as progesterone and related steroids, can precipitate symptoms, as can low-calorie and low-carbohydrate diets, large amounts of alcohol, or smoking. Stress resulting from an infection, another illness, surgery, or a psychologic upset is also sometimes implicated. Usually a combination of factors is involved. Sometimes the factors that cause an attack cannot be identified.

Symptoms

Symptoms occur as attacks lasting several days or weeks, and sometimes even longer. Such attacks usually first appear after puberty. In some women, attacks develop during the second half of the menstrual cycle.

Abdominal pain is the most common symptom. The pain can be so severe that the doctor may mistakenly think that abdominal surgery is needed. Gastrointestinal symptoms include nausea, vomiting, constipation or diarrhea, and abdominal bloating. The bladder may be affected, making urination difficult and sometimes resulting in an overfull bladder. A rapid heart rate, high blood pressure, sweating, and restlessness are also common during attacks; interference with sleep is typical. High blood pressure can continue after the attack.

All of these symptoms, including the gastrointestinal ones, result from effects on the nervous system. Nerves that control muscles can be damaged, leading to weakness, usually beginning in the shoulders and arms. The weakness can progress to virtually all the muscles, including those involved in breathing. Tremors and seizures may develop.

Recovery from symptoms may occur within a few days, although complete recovery from severe muscle weakness may take several months or years. Attacks are rarely fatal; however, in a few people, attacks are disabling.

Diagnosis and Prognosis

The severe gastrointestinal and neurologic symptoms resemble those of many more common disorders. Laboratory tests performed on samples of urine show increased levels of two heme precursors (delta-aminolevulinic acid and porphobilinogen). Levels of these precursors are very high during attacks and remain high in people who have repeated attacks. The precursors can form porphyrins, which are reddish in color, and other substances that are brownish. These turn the urine dark, especially after exposure to light.

Relatives without symptoms can be identified as carriers of the disorder by measuring porphobilinogen deaminase in red blood cells or sometimes by DNA testing. Diagnosis before birth is also possible but usually is not needed because most affected people never get symptoms.

Prevention and Treatment

Attacks of acute intermittent porphyria can be prevented by maintaining good nutrition and avoiding the drugs that can provoke them. Crash diets to lose weight rapidly should be avoided. Heme can be given to prevent attacks. Premenstrual attacks in women can be prevented with one of the gonadotropin-releasing hormone agonists used to treat endometriosis (see Section 22, Chapter 245), although this treatment is still investigational.

People who have attacks of acute intermittent porphyria are often hospitalized for treatment of severe symptoms. People with severe attacks are treated with heme given intravenously. Blood and urine levels of delta-aminolevulinic acid and porphobilinogen are promptly lowered and symptoms improve, usually within several days. If treatment is delayed, recovery takes longer, and some nerve damage may be permanent.

Glucose given intravenously or a diet high in carbohydrates can also be beneficial, particularly in people whose attacks are brought on by a low-calorie or low-carbohydrate diet, but these measures are less effective than heme. Pain can be controlled with drugs (such as opioids) until the person responds to heme or glucose.

Nausea, vomiting, anxiety, and restlessness are treated with a phenothiazine for a short time. Insomnia may be treated with chloral hydrate or low doses of a benzodiazepine but not a barbiturate. An overfull bladder may be treated by draining the urine with a catheter.

The doctor ensures that the person does not take any of the drugs known to precipitate an attack, and--if possible--addresses other factors that may have contributed to the attack. Treatment of seizures is problematic, because almost any anticonvulsant would worsen an attack. Beta-blockers may be used to treat rapid heart rate and high blood pressure but are not used in people who are dehydrated, in whom a rapid heart rate is needed to maintain the blood circulation.