Acute intermittent porphyria

Acute intermittent porphyria (AIP) is a rare autosomal dominant inherited disorder characterized by a partial deficiency of porphobilinogen deaminase, which leads to the accumulation of porphyrin precursors and porphyrins in the body.

Most individuals remain asymptomatic, but symptoms can be triggered by use of certain drugs, steroid hormones, or alteration of nutritional status.

The most common presenting features include pain in the abdomen, extremities, back, and chest, tachycardia, hypertension, nausea, vomiting, constipation, and peripheral motor neuropathy.

The pain is neuropathic and not accompanied by inflammation.

Red or brownish urine results from marked increases in urinary excretion of heme pathway intermediates. Porphyrins are reddish and fluoresce when exposed to long-wave ultraviolet light. Porphobilinogen is colorless but degrades on standing to form porphyrins and brownish pigments.

AIP is a rare genetic disorder characterized by a partial deficiency of porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase, the third enzyme in the heme biosynthetic pathway. When exacerbating factors induce heme biosynthesis, the hepatic enzyme delta-aminolevulinic acid (ALA) synthase is upregulated. This stimulates increased production of ALA and porphobilinogen (PBG). Because patients with AIP have a partial deficiency of PBGD, which is downstream of ALA synthase in the heme biosynthesis pathway, they cannot convert all of the ALA and PBG into hydroxymethylbilane, the next compound in the heme biosynthesis pathway. Consequently, the porphyrin precursors ALA and PBG accumulate in the body.[1]Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8:201-14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562648 http://www.ncbi.nlm.nih.gov/pubmed/26366103?tool=bestpractice.com  Urinary excretion of ALA, PBG, and porphyrins is increased when this occurs.

More than 400 mutations of the gene encoding PBGD have been identified in different AIP families.[2]Chen B, Solis-Villa C, Hakenberg J, et al. Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease. Hum Mutat. 2016 Nov;37(11):1215-22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063710 http://www.ncbi.nlm.nih.gov/pubmed/27539938?tool=bestpractice.com Most of those who inherit one copy of these mutations remain asymptomatic with little or no elevation in ALA, PBG, and porphyrins, but the condition can be activated after puberty by some drugs and steroid hormones (especially progestins) or by reducing dietary calorie intake.