The effects of inhibition of haem biosynthesis by griseofulvin on intestinal iron absorption.

The relationship between haem biosynthesis and intestinal iron absorption in mice was investigated by ascertaining the effect of the haem synthesis inhibitor, griseofulvin, on duodenal iron absorption using both in vivo and in vitro measurements. Urinary 5-aminolaevulinic acid levels were increased within 24 hr of feeding mice with griseofulvin diet (2.5% w/w), with more marked increases seen after 3-7 days. Urinary porphobilinogen levels also showed a similar trend. In vivo intestinal iron absorption was significantly reduced (P<0.05) in experimental mice, mainly due to reduction in the transfer of 59Fe from the enterocytes to the portal circulation. In vitro studies using isolated duodenal fragments also exhibited marked decreases in both iron uptake and Fe (III) reduction. Changes in mucosal Divalent Metal Transporter 1 (DMT-1), Dcytb and Ireg1 (iron regulated protein 1) mRNA levels paralleled the changes in iron absorption. The reduction in iron absorption after griseofulvin treatment was normalised when mice were simultaneously injected with haem-arginate. These data support the hypothesis that intermediates in haem biosynthesis, particularly 5-aminolaevulinic acid, regulate intestinal iron absorption.

Erythropoietin treatment in the neuropsychiatric porphyrias.

BACKGROUND: In a previous report, 31 patients with neuropsychiatric porphyria were studied and nine of these patients were anaemic in association with inappropriately low serum erythropoietin levels. We were also able to demonstrate that treatment with erythropoietin in non-porphyric patients (mainly diabetic patients with autonomic neuropathy) significantly reduced urinary delta-aminolaevulinic acid levels. METHODS: We treated six porphyric patients, five of whom were anaemic, with recombinant human erythropoietin (1000-2000 IU thrice weekly). They were all in clinical but not biochemical remission. Full blood count, including reticulocytes and platelets, urinary delta-aminolaevulinic acid, porphobilinogen and total porphyrins were measured monthly. Baseline serum ferritin, vitamin B(12), folate and C-reactive protein levels were all within the normal range and serum creatinine did not exceed 126 micromol/l. RESULTS: After 3 months of treatment, the average baseline haemoglobin increased significantly (p=0.01). When treatment was stopped, the haemoglobin decreased and after 3 months pre-treatment, haemoglobin levels were reached. Urinary delta-aminolaevulinic acid, porphobilinogen and porphyrin levels all tended to decrease during treatment with erythropoietin, but the difference between baseline and 3 months of erythropoietin was statistically significant only for porphobilinogen (p=0.03). The severity of porphyria attacks was reduced and the quality of life increased during treatment with erythropoietin. CONCLUSION: We conclude that in some porphyric patients treatment with erythropoietin reduces urinary delta-aminolaevulinic acid, porphobilinogen and porphyrin levels with an increase in well-being and a reduction in the severity of porphyria attacks.

Serum erythropoietin levels may be inappropriately low in the acute neuropsychiatric porphyrias.

BACKGROUND: Patients with the acute porphyrias may develop renal failure and autonomic dysfunction. Renal damage and sympathetic failure may both cause erythropoietin (EPO) deficiency. In this study, we have investigated serum erythropoietin levels and autonomic function in patients with acute porphyria in clinical remission. METHODS: Serum erythropoietin levels and the corresponding haemoglobin (Hb) were assayed in 31 patients with acute porphyria and were compared to 15 type 1 diabetic patients with autonomic neuropathy, 23 patients with iron-deficiency anaemia and 18 healthy individuals. RESULTS: 9 out of 31 porphyric patients showed a normochromic normocytic anaemia with normal ferritin levels. Three patients had borderline-raised serum creatinine levels, and one of them was anaemic. Autonomic function was investigated in seven patients, six of them being anaemic, and the results were normal. Patients with iron-deficiency anaemia showed the expected increase in serum erythropoietin levels in response to a decreasing haemoglobin (r=-0.86, p<0.001). Patients with porphyria had inappropriately low serum erythropoietin levels for the degree of anaemia compared to iron-deficiency patients (p<0.001) although there was still a significant increase in serum erythropoietin with decreasing haemoglobin levels (r=-0.46, p=0.01). In contrast, diabetic autonomic neuropathy patients demonstrated a significant decrease in serum erythropoietin with decreasing Hb levels (r=+0.53, p=0.05). CONCLUSIONS: Patients with acute porphyria may have inappropriately low levels of EPO. In contrast to the diabetic patients, this does not appear to be due to autonomic neuropathy but it may reflect mild renal tubular impairment.