Biomedical subjects
Publications and source records attributed to K E McColl.
A 22 year old Caucasian girl living in Glasgow presented with eye disease due to Vitamin A deficiency. There was no evidence of liver disease or malabsorption and the vitamin deficiency was found to be due to her bizarre dietary habit.
The acute porphyrias consists of a group of pharmacogenetic disorders of haem biosynthesis which are characterised by attacks of abdominal pain and neurological dysfunction. Although the genetic and biochemical basis of these diseases is now well established, the pathogenesis of the clinical manifestations remains speculative. Symptomatic and supportive therapy remain an important part of the management of the acute attacks. High carbohydrate intake and parenteral haematin administration are the only proven therapies that can modify an attack, both clinically and biochemically. However, haematin therapy does not provide satisfactory prophylaxis. The future use of luteinising hormone-releasing hormone (LHRH) agonists to prevent recurrent attacks in selected female patients is still under investigation.
A woman with acute intermittent porphyria and a man with variegate porphyria developed chronic renal failure in middle age. After periods on haemodialysis, both received successful cadaveric renal transplants. On the basis of animal porphyrinogenicity studies prednisolone and azathioprine were used in preference to cyclosporin as immunosuppressive agents. Neither of the patients showed any evidence of activation of their porphyria during, or following, transplantation. The findings in these two patients and a review of two previous reports indicate that acute porphyria is not a contraindication to renal transplantation.
In healthy human volunteers, a single oral dose of enprostil (35 micrograms) inhibited basal gastric acid output by a mean of 71 percent, pentagastrin-stimulated output by 46 percent, sham-meal-stimulated output by 48 percent, and histamine-stimulated output by 16 percent. In each case, there was a reduction in both the volume and acidity of the gastric juice. Pepsin output was unchanged. Although enprostil increased the gastric pH, it did not induce basal or post-prandial hypergastrinemia. In patients with hypergastrinemia secondary to achlorhydria, enprostil lowered the basal gastrin level and reduced or abolished the post-prandial gastrin rise in a dose-related fashion. Enprostil reduces basal and stimulated gastric acid secretion and inhibits gastrin release.
Acute porphyria afflicts a large kindred in Chester that stems from a marriage in 1896 that has produced 200 descendants; this is the largest porphyric kindred to be identified in the United Kingdom. Six members aged 51 or under died from the condition over the past eight years. The diagnosis of porphyria was overlooked in some as the symptoms may mimic those of other acute illnesses, so that incomplete or incorrect death certificates have been issued. Psychosis, hypertension, and renal complications are particularly common. The porphyric members of the kindred show a previously undescribed hereditary disorder in which the characteristic enzymatic defects of acute intermittent porphyria and variegate porphyria coexist in the same subject. Acute porphyria is poorly understood by hospital and general practitioners, and this has caused anxiety in the kindred. A register of the kindred has been established, and families at risk should be offered biochemical screening, education, and genetic counselling.
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The potency and duration of the antisecretory action of zaltidine, a novel H2-receptor antagonist, have been examined in healthy volunteers and in patients with previous duodenal ulceration. In eight healthy male volunteers single oral doses of 5 mg, 25 mg and 100 mg produced dose-related inhibition of basal and pentagastrin-stimulated acid output (M.A.O.) with an estimated ID50 of 40 mg for the latter. In eight subjects with duodenal ulceration single 100 mg and 200 mg doses produced 85% and 97% inhibition of M.A.O. at peak (3 h post-dose) and 20% and 23% inhibition at 24 h, respectively; inhibition of basal acid output was 97% at 3 h and 50% at 24 h with both doses. The long duration of action of zaltidine is ascribed to its relatively slow elimination from the plasma.
A 56-yr-old man presented with a photosensitive bullous dermatosis 1 yr after commencing hemodialysis. Urinary porphyrin levels were normal and fecal porphyrin levels only minimally increased, but the plasma uroporphyrin concentration was markedly elevated, being higher than that normally occurring in porphyria cutanea tarda. The high plasma uroporphyrin level was thought to result from the combined effects of increased porphyrin production and failure of adequate clearance by hemodialysis. Chronic alcohol ingestion, methyldopa therapy and elevated iron and aluminum levels may have contributed to the porphyrin overproduction. Charcoal hemoperfusion proved unhelpful in lowering the plasma uroporphyrin concentration.
A previously unrecognised form of acute porphyria has been identified in a large family in Chester, UK. Patients presented with attacks of neurovisceral dysfunction and none had experienced cutaneous photosensitivity. Biochemically, the excretion pattern of haem precursors varied between individuals; some had a pattern typical of acute intermittent porphyria, others showed that of variegate porphyria, and some had an intermediate pattern. Studies of the enzymes of haem biosynthesis in peripheral blood cells showed a dual enzyme deficiency, with reduced activity of both porphobilinogen deaminase, as seen in acute intermittent porphyria, and protoporphyrinogen oxidase, as seen in variegate porphyria. The genetic basis of this dual form of acute porphyria and its relation to the other acute porphyrias are not clear.
The effect of cimetidine (CMT; 400 mg twice daily) and matching placebo on the enzyme-inducing properties of carbamazepine (CBZ; 200 mg at night for 15 days) was studied in seven healthy male volunteers. CMT alone had no significant effect on antipyrine kinetics, urinary 6 beta-hydroxycortisol excretion or leucocyte delta-aminolaevulinic acid synthase (ALA.S) activity. CBZ increased leucocyte ALA.S activity by 204% following 1 week's treatment (P less than 0.001). Thereafter, ALA.S activity fell despite continued CBZ administration. Concomitant CMT did not influence this response. Antipyrine clearance and urinary 6 beta-hydroxycortisol excretion were both increased by CBZ after 2 weeks' treatment (P less than 0.01). CMT blocked CBZ induction of antipyrine metabolism but the rise in urinary 6 beta-hydroxycortisol excretion was unaffected. Plasma CBZ concentrations 10, 14 and 18 h following the 8th and 15th doses were higher when CMT was taken concurrently (P less than 0.05). CBZ half-life fell by 36% and clearance rose by 29% (both P less than 0.001) with placebo and by 10% and 7% (both NS) when CMT was taken concurrently. CMT inhibits CBZ auto- and hetero-induction in man. Epileptic patients receiving CBZ chronically may be at risk of toxicity if CMT is also prescribed.
Two hundred and thirteen patients were studied in a double-blind trial of cimetidine versus placebo in the treatment of acute upper gastrointestinal haemorrhage. One hundred and six patients were randomly allocated to receive cimetidine and 107 to receive placebo. There was no significant reduction in transfusion requirements, incidence of further haemorrhage, length of stay in hospital, or mortality in the treated group. There was no subgroup of patients with acute upper gastrointestinal bleeding which appeared to benefit from treatment with cimetidine.
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Charcoal haemoperfusion has been advocated as a means of removing delta aminolaevulinic acid, which accumulates in attacks of acute intermittent porphyria. A woman presented with acute intermittent porphyria unresponsive to conventional treatment and with pain that was difficult to control. Charcoal haemoperfusion was performed in series with haemodialysis for two hours daily on four consecutive days. Although during this treatment serum and urinary concentrations of delta aminolaevulinic acid and porphobilinogen were considerably reduced, they had returned to pretreatment values 24 hours after the end of treatment. Abdominal pain was not relieved. Although a longer course of treatment might have had a more favourable outcome, this seems unlikely in view of the rapid rebound of serum concentration of delta amino-laevulinic acid after each haemoperfusion.
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Studies of iron metabolism were made in 24 patients following surgery under general anaesthesia. No postoperative complications occurred. There was a marked fall in serum iron in all patients on the first postoperative day (P less than 0.001) which remained significantly depressed even at the seventh postoperative day. The total iron binding capacity fell progressively to reach the lowest levels on the third postoperative day, returning to normal levels by the end of the study. Serum ferritin concentration rose significantly in a reciprocal pattern to the changes in serum iron. This study highlights the limitation of iron studies in peripheral blood in postoperative patients.
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In a retrospective survey of patients who have had a proven attack of acute intermittent porphyria (AIP) in the West of Scotland a highly significant association (p less than 0.001) was observed between AIP and the development of early-onset chronic renal failure. Six patients with AIP and chronic renal failure arising in early middle-age are described. As no other cause could be attributed to the renal failure three possible causal links between these two conditions were considered, namely, enhanced susceptibility to analgesic nephropathy, porphyria-induced hypertension, and nephrotoxic effects of porphyrins and their precursors. We suggest that porphyria-induced hypertension is the most important factor in causing early-onset chronic renal failure in acute intermittent porphyria.
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