Etiology

AIP results from the autosomal dominant inheritance of a deficiency in porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. The PBGD gene is located on chromosome 11. More than 400 different mutations of this gene have been identified in different AIP families. These mutations include missense, nonsense, and splicing mutations, and insertions and deletions.[2][8]

AIP remains latent in most heterozygotes. These people are identified in family studies by measuring erythrocyte PBGD activity or, more reliably, by DNA studies. Pathogenic HMBS mutations have been identified in some families with no known cases of AIP.[2][7] Some heterozygotes may develop a variety of nonspecific symptoms after puberty. 

Triggers for an AIP attack include certain drugs, alcohol, infections, low calorie intake, or changes in sex hormones during pregnancy or the menstrual cycle.[1] These factors induce delta-aminolevulinic acid synthase (ALAS1), the rate-limiting enzyme for heme biosynthesis in the liver, and cytochrome P-450 (CYP) enzymes. CYPs are heme-containing enzymes that are especially abundant in the liver and require most of the heme synthesized in the liver.[9] With induction of ALAS1, the deficiency of PBGD becomes significant and then large amounts of the porphyrin precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), accumulate in the body.[4]

Pathophysiology

With the partial block in heme synthesis at the PBGD reaction stage, a concurrent induction of ALAS1 results in accumulation and marked increases in urinary excretion of ALA, PBG, and porphyrins. ALA and PBG are colorless, whereas porphyrins are reddish in color and fluorescent. PBG can spontaneously form porphyrins and can degrade to form porphobilin, a brownish pigment, often resulting in deep red urine, a hallmark of this and other acute porphyrias.

Symptoms are due to effects on the nervous system, including:

  • Peripheral and autonomic neuropathies

  • Psychiatric manifestations

  • Syndrome of inappropriate ADH secretion, which causes hyponatremia.

The mechanisms of neurologic manifestations of AIP are not well understood, but it seems likely that a heme pathway intermediate or product is neurotoxic, and ALA seems the most likely candidate.[4] Impaired availability of heme for some essential neural hemoproteins has also been suggested.[3]

Classification

Clinical definitions[3][4]

  • Clinically expressed AIP: heterozygotes with symptoms and increased PBG.

  • Biochemically expressed AIP: heterozygotes with increased PBG but no symptoms. These are often referred to as asymptomatic high excreters.

  • Latent AIP: heterozygotes without symptoms or increased PBG.

  • Homozygous AIP: rare cases that present in childhood with severe neurologic symptoms and delayed development.

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