Investigation of the 17-oxosteroids in the hepatic porphyrias

Paxton, James William (1973) Investigation of the 17-oxosteroids in the hepatic porphyrias. PhD thesis, University of Glasgow.

Abstract

During the past eighty years, there has been much clinical and experimental evidence presented by a wide variety of investigations confirming the deleterious interplay of endocrine and genetic factors in the natural history of these diseases known as the porphyriae. The porphyrin-inducing Sa-H Sb-H 17-oxosteroids that have been identified delineate one category of endogenous agents through which such an endocrine-genetic interplay may be affected in some subjects, and it is the purpose of this investigation to examine the relevance of the part played, if any, by some of these 5a-H and 5p-H 17-oxosteroids in the pathogenesis of the porphyrias in humans. Preliminary experiments included the setting-up and evaluation of methods for the measurement of four 17-oxosteroid sulphates and eight 17-oxosteroid glucuronides in urine and the measurement of their levels in urine in seventy- five normal subjects, consisting of thirty-eight males and thirty-seven females. A pattern similar to that obtained by Hamburger (1948) for the total urinary 17-oxosteroids excretion of different age groups was obtained for the individual urinary 17-oxosteroid levels in this control group. These methods were then applied to the study of the urinary levels of these 17-oxosteroids in patients suffering from acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (UP) and porphyria cutanea tarda (PCT). In total, thirty-four patients with AIP, five patients with HCP, two patients with UP and fourteen patients with PCT were investigated. Of the thirty-four patients with AIP, a total of twenty-three had elevated levels of certain of these 17-oxosteroids, especially dehydroepiandrosterone sulphate (DMAS) and aetiocholanolone glucuronide (EG) and sulphate (ES) in the urine. The seven patients with AIP who were investigated during or shortly after attack had levels of urinary 17-oxosteroids well beyond the range of the normal control group. Similar results were obtained with the five patients with HCP, with the exception that the elevations of these 17-oxosteroids were observed only in the urine of the three patients who were in attack and not in those who were in remission. In one patient with AIP and two patients with HCP from whom serial 24-hour urine specimens were obtainable, significant linear correlations were found between the values of the ratio of urinary aetiocholanolone to androsterone and the levels of 6-aminolaevulic acid (ALA) and porphobilinogen (PBG) in the individual urines. The two patients with UP who were investigated were in remission and did not show any elevations of these steroids in the urine. The fourteen patients with PCT who were studied did not show any elevations of the urinary levels of these 17-oxosteroids, but it was noted that this group tended to excrete lower levels of steroids than the similarly aged normal controls. More specific investigations were undertaken with one male patient who had suffered from several acute attacks of porphyria. During those attacks, his DMAS and EG were the predominantly raised urinary steroids. After treatment with dexamethasone, which suppresses the activity of the adrenal cortex, his clinical condition improved, his urinary oxosteroid levels fell sharply, corresponding with an equally sharp fall in urinary porphyrins and precursors (ALA and PBG). Having established these irregularities in the levels of 17-oxosteroids in the urine of some of these porphyric patients, this pathway of research was further pursued by setting up and carefully evaluating a method for estimating the four main 17-oxosteroid sulphates in plasma. As with the urinary studies, a similar control group of wide age range consisting of fifty-three males and thirty-nine females was studied initially. Some of the subjects from the control group were investigated for fluctuations due to diurnal variation and for cyclic fluctuations due to different phases of the normal menstrual cycle. Having established normal values for the concentrations of these 17-oxosteroid sulphates in plasma, investigation of their concentrations in the plasma of patients suffering from hepatic porphyria was undertaken. As with the urinary results, no elevations of the levels of these steroids beyond the normal range were observed in the plasma of patients with PCT but,in the plasma of patients with AIP, elevations of these steroids, predominantly DHAS and ES, were observed, in most cases corresponding with similar urinary elevations. These results, along with the observations of other investigations, do suggest that although the primary genetic defect may not be an endocrine one, the effects of many of the factors involved in the initiation, provocation and aggravation of the hepatic porphyrias may be mediated through interaction with an endogenous regulatory system of steroid metabolism in the liver. This interference with normal endogenous steroid metabolism may result in direct overproduction and accumulation in the liver of a steroid with strong porphyrinogenic inducing activity (perhaps aetiocholanolone or dehydroepiandrosterone) or indirectly in antagonism of the hypophysis, hypothalamus and endocrine glands which form a functional unit for the homeostatic regulation of the plasma levels of hormones. The suggestion is also put forward that dehydroepiandrosterone or a close metabolite may possibly act as a constant stimulus to haem biosynthesis in the human hepatic cell.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: R MS Smellie
• Keywords: Endocrinology
• Date of Award: 1973
• Depositing User: Enlighten Team
• Unique ID: glathesis:1973-72839
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 11 Jun 2019 11:06
• Last Modified: 11 Jun 2019 11:06
• URI: https://theses.gla.ac.uk/id/eprint/72839