Porphyrias are a group of metabolic disorders, mainly inherited, in which there are defects in the heme biosynthetic pathway that may lead secondarily to overproduction of one or more heme precursors. Heme is essential for transport of oxygen from the lungs to tissues and removal of carbon dioxide from tissues to the lungs for excretion (haemoglobin) and biotransformation (respiratory chain, cytochromes P-450, and other heme-containing enzymes). Eight different enzymes are involved in the biosynthesis of heme. The activity of the entire pathway is chiefly related to end-product repression of activity of the first and normally rate-controlling enzyme of the pathway, namely 5-aminolevulinic acid (ALA) synthase. Partial deficiency of heme leads to up-regulation of ALA synthase by several molecular mechanisms, whereas sufficiency or excess of heme leads to down-regulation of ALA synthase through effects on gene transcription, decreased stability of its mRNA, decreases in its transport into mitochondria, and decreases in half-life of the mature mitochondrial for of the synthase.
The enzyme deficiency disorders follow either an autosomal dominant, autosomal recessive or x-linked inheritance except the sporadic PCT. There are eight different forms of porphyria, non-acute and acute forms, depending on the chief site of overproduction of heme precursors. Porphyrias are classically divided into hepatic or erythopoietic types. Another useful classification is according to cardinal clinical manifestations: four of the diseases may give rise to acute attacks with neuro-visceral manifestations [the acute or inducible porphyrias AIP, VP, HCP, PP], and these are an issue concerning anaesthesia. Other forms cause cutaneous manifestations. However, for two of the diseases, namely, hereditary coproporphyria and variegate porphyria, patients may have both neuro-visceral and cutaneous manifestations. The non-acute porphyrias do not exhibit the acute symptoms of neurological disorders, abdominal pain, and electrolyte abnormalities, and in particular they are not triggered by anaesthetic agents or any drugs. Therefore they do present a serious perioperative risk.
Incidence: acute porphyric attacks hardly ever occur before puberty. They are mainly disease of women in their child-bearing years [Ages 18-50 years]. In most countries, acute intermittent porphyria is the most common and most severe form of acute porphyria, with symptomatic disease occurring in 1:10,000 to 1:20,000. In patients with psychiatric disorders, the prevalence may be higher, perhaps as high as 1:500. The prevalence of genetic defects in the hydroxymethyl bilane synthase (hmbs) gene [also known as porphobilinogen deaminase] is far higher, about 1/1,600 persons in Western Europe, emphasizing the importance of other genetic or acquired factors in pathogenesis. Both, symptomatic and asympomatic heterocygotes, have 50 percent or greater of porphobilinogen deaminase activity in the majority of patients; a total deficiency is not reconcilable with life. 90 percent of individuals with the deficiency exhibit no clinical signs. Hormonal and nutritional factors, as well as pharmacologic agents (induction of ALA (amino levulinic acid) -synthetase) may exacerbate the disorder. Initiating factors for an overproduction are infections, starvation, alcohol, induction of hepatic CYP 450 by drugs (such as barbiturates), pregnancy, hormones.
Other Symptoms: Acute attacks occur after puberty, commonly in females, cause abdominal pain, obstipation, nausea, autonomic instability with hypertension, tachycardia, neuropathy, muscle weakness, paraesthesia, neuropsychiatric abnormalities, depression, electrolyte abnormalities, haemolytic anaemia, hepatic failure, or cirrhosis.