Clinically important features of porphyrin and heme metabolism and the porphyrias

Abstract

Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic porphyrias are further subdivided into acute porphyrias and chronic hepatic porphyrias. The acute porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic porphyrias include congenital erythropoietic porphyria (Gűnther's disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria.

Figure 1

The heme biosynthetic pathway and aspects of its regulation in hepatocytes. Key roles are played by 5-aminolevulinic acid synthase-1 (ALAS1), heme oxygenase 1 (HMOX1), nuclear receptors (NRs) and hydroxymethylbilane synthase (HMBS) (also known as porphobilinogen (PBG) deaminase). Heme itself downregulates several steps in the synthetic pathway, especially ALAS1, by downregulating transcription, upregulating mRNA breakdown, blocking uptake into mitochondria and increasing Lon peptidase 1 breakdown of the mature mitochondrial enzyme. Heme upregulates HMOX1, mainly by increasing its transcription through binding to Bach1, a tonic repressor. HMBS is present in low amounts and becomes rate controlling when ALAS1 is induced. Fifty percent deficiency of HMBS, the defect in acute intermittent porphyria (AIP), can lead to critical deficiency of heme and uncontrolled induction of ALAS1. Heme administered intravenously is taken up well by hepatocytes and can replete heme pools rapidly and correct the defects caused by HMBS and other synthetic enzyme deficiencies. More recent studies in cell culture models suggest that heme excess may exert additional effects on other enzymes in the synthetic pathway, as suggested by the + and − symbols in the figure (World J Gastroent 19 (10): 1593). However, whether such effects are clinically relevant remain uncertain.