Studies on the Acute Hepatic Porphyrias

Yeung Laiwah, Albert A. C (1985) Studies on the Acute Hepatic Porphyrias. MD thesis, University of Glasgow.

Abstract

This thesis consists of three sections. The first section is a general description of porphyrins and biochemical control of haem biosynthesis followed by an up-to-date review of the acute hepatic porphyrias and their clinical management, with particular emphasis on acute intermittent porphyria (AIP). The second section addresses itself to the pathogenesis of the neuropathy of AIP. Following a critical review of the histopathological and biochemical work on the subject the results of a study on the cardiovascular autonomic function in AIP are discussed. Objective evidence for parasympathetic and sympathetic dysfunction during an acute attack is provided. Moreover, there is suggestion of parasympathetic involvement both in patients who have fully recovered from the acute episodes and asymptomatic latent cases. These findings support the electrophysiological results of Mustajoki and Seppalainen (1975). Using two different histochemical techniques, cytochrome oxidase activity was found to be markedly depressed in muscle biopsies taken from AIP patients during an acute attack. Since cytochrome oxidase plays a vital role in the terminal oxidative phosphorylation pathway, the possibility of a myopathic component in the muscle weakness, hitherto attributed to the neuropathy, is considered. But more significantly, depression of cytochrome oxidase activity in muscle tissue suggests that this might be the case in nerve cells. Further support for this concept comes from other workers who have shown that the activity of the cytochrome-P450-dependent mixed-function oxidase system is also depressed in porphyric patients. The cytochrome oxidase study is followed by a clinico-pathological discussion on the autopsy findings of a 31-year old AIP patient who died of the disease. Detailed documentation of the patient's clinical course and the purposeful neuropathological autopsy carried out provided us with a rare opportunity to investigate further the relative roles of demyelination and axonal degeneration in the pathogenesis of the disease. It was indeed surprising when independent review of the autopsy material by two experienced neuropathologists failed to reveal any of the characteristic morphological changes previously described. The newly discovered association between early-onset chronic renal disease and AIP is discussed along three main possibilities: analgesic-induced nephropathy, hypertension-related renal disease and cytotoxic effects of porphyrin precursors on the kidneys. Analgesic-induced nephropathy could be satisfactorily excluded. On balance evidence is in favour of hypertension-related renal disease although a local toxic effect by porphyrin precursors cannot be entirely excluded. A strong case can be made for the porphyria-associated hypertension to the neurogenic in type. Many AIP patients with severe abdominal pain fail to respond to large dosages of opiate analgesics. A study was performed to determine whether the porphyric pain was truly resistant to opiates. It was found that if the patient failed to respond to the usual therapeutic dosage of one of three opiates: pethidine, morphine and buprenorphine, increasing the amount of drug administered did not improve the response rate. In 1981, I observed that the pupils of a porphyric patient in a severe attack failed to undergo miosis after parenteral administration of large doses of morphine; yet they retained a normal response to accommodation and light stimulation. The significance of this finding, only recently appreciated, indicate the possibility of either dysfunction or depletion of the mu-opioid receptors in the optic nervous system. (Abstract shortened by ProQuest.).

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Keywords: Medicine
• Date of Award: 1985
• Depositing User: Enlighten Team
• Unique ID: glathesis:1985-77358
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 11:53
• Last Modified: 14 Jan 2020 11:53
• URI: https://theses.gla.ac.uk/id/eprint/77358