title: The acute hepatic porphyrias
Creators: name: McColl, Kenneth E.L.
Publisher: name: University of Glasgow
Year: 1981
Subjects: subject: Biochemistry, hepatic porphyrias, (AHPs).

description: The acute hepatic porphyrias are the result of hereditary partial deficiencies of individual enzymes in the pathway of haem biosynthesis. Seven enzymes are known to be involved in the pathway, converting glycine and succinyl CoA first to porphyrin precursors and then to porphyrins and finally to haem. The rate of the process is regulated by the initial enzyme, delta-aminolaevulinic acid (ALA) synthase,which is under negative feedback control, by haem. The partial block in this pathway, in each of the acute porphyrias,results in compensatory increased activity of ALA synthase and,consequently,overproduction of porphyrins and precursors formed prior to the deficient enzyme. Patients with acute porphyria generally enjoy good health,but exposure to certain recognised factors, namely specific drugs, alcohol, hormones and fasting; may precipitate severe clinical attacks characterized by gastro-intestinal symptoms, psychiatric disturbances and neuropathy. All of the systemic manifestations of the attack are thought to be explained by neurological dys function,but the mechanism by which the abnormal haem biosynthesis causes the neuropathy is not known. Following a general description of haem biosynthesis and the porphyrias, this thesis concentrates on the management of acute hepatic porphyria studying, in turn, the detection of subjects with the genetic trait, the factors which may precipitate attacks in these subjects and the treatment of patients in established attack. Much of the work presented is based upon the ability to measure the activities of the individual enzymes of haem biosynthesis in human peripheral blood cells. The mitochondrial enzymes, ALA synthase, coproporphyrinogen oxidase and ferrochelatase, are measured in leucocytes and the cytosolic enzymes, ALA dehydratase, uroporphyrinogen-1-synthase (URO synthase) and uroporphyrinogen decarboxylase, in erythrocytes. The measurement in peripheral blood cells of the activities of both the rate-controlling enzyme, ALA synthase, and the appropriate genetically deficient intermediate enzyme, is shown to be a sensitive and specific means of detecting latent cases of acute porphyria,the majority of whom have normal excretion of porphyrins and precursors. Enzymatic screening of affected families confirms that the genetic trait is inherited in an autosomal dominant sex-independent manner. The family studies also demonstrate that the vast majority of subjects with the trait remain clinically latent, and the reason why the minority of patients experience clinical manifestations is examined. The activity of the partially deficient enzyme is similar in latent and manifest cases, but ALA synthase activity is higher in patients who have experienced an attack and this may reflect higher circulating levels of endogenous inducing agents. Drugs are an important exogenous precipitating factor for acute porphyria, and an important aspect of the prevention of attacks is the identification of potentially porphyrinogenic drugs. The testing of 26 commonly prescribed drugs, by assessing their effect on hepatic ALA synthase activity in rats, is described. The mechanism by which drugs stimulate ALA synthase activity is examiaed with particular reference to the role of induction of the mixed function oxidase enzyme (MFO) system. A close correlation is noted between induction of the MFO system, as reflected in increased hepatic cytochrome P450 content, and increased activity of ALA synthase, though not the converse. Sequential studies following commencement of phenytoin administration to rats show that the rise in ALA synthase activity is transitory and coincides with the rise in hepatic cytochrome P450 content which is maintained. These observations indicate that induction of the MFO system demands increased ALA synthase activity to provide the additional haem for synthesis of the haemoprotein, cytochrome P450. (Abstract shortened by ProQuest.).