Role of delta-aminolevulinic acid in the symptoms of acute porphyria

Abstract

Background: Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative.

Methods: We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome.

Results: Although each of these conditions has characteristic urine biochemistry, all exhibit excess delta-aminolevulinic acid. Moreover, in all, treatment with hemin reduces delta-aminolevulinic acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective.

Conclusions: There is now convincing evidence that delta-aminolevulinic acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-aminolevulinic acid synthase-1, the enzyme that catalyzes delta-aminolevulinic acid formation. Delta-aminolevulinic acid synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria.

Keywords: Abdominal pain; Acute porphyria; Ayurveda; Delta-aminolevulinic acid; Lead poisoning.

Figure 1

Schematic pathway of heme synthesis and utilization, showing the enzymes mediating formation of delta-aminolevulinic acid, porphobilinogen and the initial porphyrin (uroporphyrinogen), respectively. Also shown is the regulatory feedback loop involving the end-product of the pathway, heme, and delta-aminolevulinic acid synthase activity. Inhibition of delta-aminolevulinic acid dehydratase by lead (Pb⁺⁺) is indicated.

Figure 2

Plain film of the abdomen showing two radio-opaque objects, ca. 8 mm in diameter, in the proximal colon.

Figure 3

Profile of heme precursors in urine for individual types of acute porphyria, lead poisoning and non-specific porphyrinuria. The bars are not to scale. They represent the general pattern of heme precursor excretion in individual disturbances of the pathway. The increases are shown relative to the upper limit of normal (horizontal dashed line).