Acute intermittent porphyria

Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common form of porphyria (porphyria cutanea tarda being the most common). Its incidence is estimated to be between 5 and 10 in 100,000, but this is likely underestimated because of positive cases not being induced, and long periods of latency, with an estimation that it is latent in 90% of cases.

Mechanism of disease

A Swedish study indicated that approximately 90% of cases of acute intermittent porphyria are due to a mutation that causes decreased amounts of the enzyme, and to a lesser degree by a mutation that causes decreased activity of each enzyme molecule.

Under normal circumstances, heme synthesis begins in the mitochondrion, proceeds into the cytoplasm, and finishes back in the mitochondrion. However, without porphobilinogen deaminase, a necessary cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphobilinogen accumulates in the cytoplasm.

Additional factors must also be present such as hormones, drugs, and dietary changes that trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain, constipation, and muscle weakness.

Patients with AIP are commonly misdiagnosed with psychiatric diseases. Subsequent treatment with anti-psychotics increases the accumulation of porphobilinogen, thus aggravating the disease enough that it may prove fatal.

It should not be mistaken that the enzyme porphobilinogen deaminase could also be called hydroxymethylbilane synthase. Gene mutation located on chromosome 11q23.3. Mutations include deletions, inversions, and translations.

Symptoms

Symptoms in AIP can be variable. They include:

• Abdominal pain which is severe and poorly localized (most common, 95% of patients experience)
• Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine)
• Peripheral neuropathy (patchy numbness and paresthesias)
• Proximal motor weakness (usually starting in upper extremities which can progress to include respiratory impairment and death)
• Autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia, hypertension, sweating, restlessness and tremor)
• Neuropsychiatric symptoms (anxiety, agitation, hallucination, hysteria, delirium, depression)
• Electrolyte abnormalities (Hyponatremia may be due to hypothalamic involvement leading to SIADH that may lead to seizures).

Unlike other porphyrias, rash is not typically seen in AIP.

Treatment

A high-carbohydrate (10% glucose) infusion is recommended, which may aid in recovery. If drugs have caused the attack, discontinuing the offending substances is essential. Infection is one of the top causes of attacks and requires vigorous treatment. Pain is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated early as medically possible due to its severity. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls.

Hematin and heme arginate are the drugs of choice in acute porphyria, in the United States and the United Kingdom, respectively. These drugs need to be given very early in an attack to be effective. Effectiveness varies among individuals. They are not curative drugs, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare but can be serious. These heme-like substances, in theory, inhibit ALA synthase and, hence, the accumulation of toxic precursors. In the United Kingdom, supplies of this drug are maintained at two national centers. In the United States, one company manufactures Panhematin for infusion. The American Porphyria Foundation has information regarding the quick procurement of the drug.

Patients with a history of acute porphyria are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms, a result of which may be that they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated. An attack of acute intermittent porphyria may be precipitated by one of the "four Ms": medication, menstruation, malnutrition, maladies.

Patients that experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the gut. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system. In these cases, treatment with long-acting opioids may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Depression often accompanies the disease and is best dealt with by treating the offending symptoms and, if needed, the judicious use of anti-depressants. Earl Campbell from University of Maryland performed the first successful clinical trial. Although results for this trial are still undergoing rigorous testing.

Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: Barbiturates and Primidone must be avoided as they commonly precipitate symptoms. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control.

Urine of AIP sufferers may turn dark purple when exposed to ultraviolet light and air after 24 hours of exposure. The colorless porphobilinogen is changed to the dark colored porphobilin due to oxygen exposure. In this condition, there is no release of red urine and no red discoloration in the patient's skin due to the lack of porphyrin ring synthesis all together during acute attacks.

Famous sufferers

One of the many hypothesized diagnoses of the artist Vincent van Gogh is that he and his siblings, in particular his brother Theo, suffered from AIP and syphilis. Another theorized sufferer was King George III of the United Kingdom who even had a medallion struck to commemorate his "curing". His great-great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria in 1968.

Popular culture

• In Season 7, Episode 9 of Scrubs, "My Dumb Luck", a patient has this disorder. J.D. diagnosed the disease when he accidentally left the patient's urine sample outside where it turned purple.
• In Season 1, Episode 21 of CSI, "Justice is Served", a nutritionist, Dr. Susan Hillridge has been murdering and removing the organs of her victims. After drying the organs, she grinds them and mixes the powder into protein shakes and drinks as a treatment for her porphyria.
• In Series 4, Episode 2 of Doc Martin, "Uneasy Lies the Head", the headmaster is diagnosed with AIP after displaying erratic behavior, constipation, and a urine sample being left in a window sill and turning blue.
• In Season 1, Episode 22 of House, M.D., "Honeymoon", House diagnoses his ex-girlfriend's husband with AIP by testing a urine sample which he collected after stabbing a syringe into his bladder, and moving the sample closer to 2 lamps (i.e., light sources).

References