Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs)

Abstract

The acute hepatic porphyrias include four disorders: acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], and the rare porphyria due to severe deficiency of ALA dehydratase [ADP]. In the USA, AIP is the most severe and most often symptomatic. AIP, HCP, and VP are due to autosomal dominant genetic abnormalities, in which missense, nonsense, or other mutations of genes of normal hepatic heme biosynthesis, in concert with other environmental, nutritional, hormonal and genetic factors, may lead to a critical deficiency of heme, the end-product of the pathway, in a small but critical 'regulatory pool' within hepatocytes. This deficiency leads to de-repression of the first and normally rate-controlling enzyme of the heme synthetic pathway, delta- or 5-aminolevulinic acid [ALA] synthase-1, and thus to marked up-regulation of this key enzyme and to marked hepatic overproduction of ALA. In addition, except for ADP, there is marked overproduction as well of porphobilinogen [PBG], the intermediate immediately downstream of ALA in the synthetic chain, and, especially in HCP and VP, also porphyrinogens and porphyrins farther down the pathway. The major clinical features of the acute porphyrias are attacks of severe neuropathic-type pain. Pain is felt first and foremost in the abdomen but may also occur in the back, chest, and extremities. Attacks are more common in women than in men [ratio of about 4:1], often accompanied by nausea, vomiting, constipation, tachycardia, and arterial hypertension. Hyponatremia may also occur. Some patients also describe chronic symptoms of pain, anxiety, insomnia, and others.

Keywords: 5-aminolevulinic acid; 5-aminolevulinic acid synthase; Acute hepatic porphyrias; Acute porphyric attacks; Heme; Hydroxymethylbilane synthase; Porphobilinogen [deaminase]; Porphyrias; Porphyrins.

Fig 1:. Summary of the Heme Synthetic Pathway and Sites of Defects in the Porphyrias

Fig. 2:. The Regulatory Heme Pool and Key Roles of Heme in Regulation of Expression of Hepatic ALA Synthase-1

Key roles are played by ALA Synthase-1 [ALAS1], heme oxygenase-1 [HMOX1], nuclear receptors [NRs], and hydroxymethylbilane [HMB] synthase [HMBS]. Heme itself downregulates several steps in the synthetic pathway, especially ALAS1, as shown in the figure, by down-regulating transcription (minus sign, −), up-regulating mRNA breakdown (plus sign, +), blocking uptake into mitochondria (−), and increasing Lon peptidase 1 breakdown of the mature mitochondrial enzyme (+). Heme up-regulates HMOX1 (+), mainly by increasing its transcription through binding to Bach1, a b-zip protein that binds DNA, and a tonic repressor of HMOX1. HMBS is present in relatively low amounts, compared to other enzymes in the biosynthetic pathway down-stream of ALAS1, and HMBS becomes rate-controlling for heme synthesis when ALAS1 is induced. 50% deficiency of HMBS, the defect in acute intermittent porphyria (AIP), can lead to critical deficiency of heme and uncontrolled induction of ALAS1. Such induction may also occur, albeit less often and less severely, when there are inherited or acquired defects in coproporphyrinogen oxidase (CPOX) or protoporphyrinogen oxidase (PPOX). Heme administered intravenously is taken up by hepatocytes, and can replete heme pools rapidly and transiently down-regulate ALAS1 and correct the defects caused by HMBS, CPOX, or PPOX deficiency. [Other abbreviations: BVR, biliverdin reductase; CO, carbon monoxide; Copro’gen, coproporphyrinogen III; Gly, glycine; PBG, porphobilinogen; Proto’gen, protoporphyrinogen IX; Succ CoA, succinyl coenzyme A; UROD, uroporphyrinogen decarboxylase; Uro’gen, uroporphyrinogen]