Porphyria

Background

• Porphyrias are inherited and/or acquired disorders of in which there are enzyme deficiencies involved in heme biosynthesis.
• Heme is a component of many essential hemoproteins, such as hemoglobin, myoglobin and cytochromes, including the cytochrome P450 enzymes
• The first enzyme in the heme production pathway is ALA synthase (ALAS), which controls the rate of heme synthesis in the liver. This enzyme is down-regulated by heme.
• The enzyme deficiencies in porphyria limit the capacity of the liver to increase heme synthesis.
• When drugs, hormones or other factors that induce ALAS and CYPs are given, ALA and porphobilinogen (PBG) are overproduced and accumulate, and a neurovisceral attack may develop

Clinical Features

• Gastrointestinal symptoms: Acute abdominal pain occurs in about 85-90% of attacks and is neurologic in origin. It can be associated with nausea, vomiting, constipation and/or diarrhea.

• Neurologic symptoms: Diffuse MSK pain and headache is also common. Objective sensory loss may be found in up to 40% of cases. Peripheral motor neuropathy is an indication of a severe and potentially life-threatening attack. Neuropathy can progress to respiratory failure and bulbar paralysis in hours or days. Sudden death, presumably from cardiac arrhythmia may occur. Bladder paresis may cause dysuria and hesitancy. CNS effects include presentations with agitation, confusion, combativeness and other acute neuropsychiatric, as well as seizure/coma/death.

Differential Diagnosis

• Consider porphyria in patients with abdominal pain that is unexplained after an initial workup has excluded common causes such as appendicitis, cholecystitis, pancreatitis, etc.
• Other clues include use of potentially porphyrinogenic drugs such as sulfonamides, barbiturates, rifampin or metoclopramide, and premenstrual symptoms in women.

Diagnosis

• Measuring urinary porphobilinogen is most important for diagnosis of acute porphyrias. Porphobilinogen (PBG) excretion is normally 0-4 mg/day, and is approximately in the same range when expressed as mg/g creatinine or even as mg/L. In an acute attack, spot urine porphobilinogen (PBG) levels are substantially increased (20-200 mg/L).
• Recurrent attacks in a patient with proven acute porphyria are usually similar and can be diagnosed on clinical grounds, and without biochemical reconfirmation.

Management

• The most effective therapy for the acute attack is hemin (Panhematin®). This drug corrects the deficiency of regulatory heme in the liver and down-regulates ALAS. The standard hemin treatment course is 3-4 mg/kg by vein once daily for 4 days. If the diagnosis is confirmed, the first dose can be given in the ED.
• Glucose loading has a similar effect, but is much less potent and effective and should be used only for mild attacks.