Increased bone marrow delta‐aminolevulinic acid synthetase activity in the acute reversible sideroblastic anemia of alcoholics

Abstract

In an effort to clarify the biochemical pathogenesis of the acute reversible siderblastic anemia of alcoholics, bone marrow delta-aminolevulinic acid (ALA) synthetase activity was measured in anemic alcoholic patients with and without pathological ring sideroblasts in their marrows and compared with the activity of this enzyme in normal subjects and in patients with idiopathic sideroblastic anemia. Mean ALA-synthetase activity measured (following addition of exogenous pyridoxal phosphate in three patients with the ring sideroblast morphologic abnormality) was 502 f 147 (SE) pmoles ALA per lo6 erythroblasts per 30 minutes, as compared with 201 f 69 in the seven alcoholic patients without pathologic sideroblastic marrow abnormalities, 169 f 32 in the six normal subjects, and 52 * 4 pmoles ALA per lo6 erythroblasts per 30 minutes in two patients with idiopathic sideroblastic anemia. Comparison of enzyme activity in the presence and absence of pyridoxal phosphate revealed that addition of this enzyme cofactor accentuated ALA-synthetase activity by an average of only 24% in the alcoholic sideroblastic group, as compared with 42% accentuation in the normal group and 8% accentuation in the idiopathic sideroblastic group. These results suggest that abnormalities in pyridoxal phosphate metabolism in alcoholics may not be of importance in the inhibition of heme biosynthesis at the level of ALA synthetase but, rather, that an enzymatic or metabolic block should be sought at a more distal site in the heme biosynthetic pathway.

Pyridoxine‐Responsive Primary Acquired Sideroblastic Anaemia

“…In erythroblasts of 14 haematologically normal controls, ALA synthase activity determined in the presence or absence of 1 mmol/l PLP was found to be between 42 and 130 pmol ALA formed/106 erythroblasts/30 min (Figure 1). These values are in accordance with values reported by other investigators using similar assay conditions (Fraser & Schachter 1980). ALA synthase activity in the patient with PASA was decreased to 13% of controls and could not be fully restored by in vitro addition of up to 1 mmol/l of PLP (Figure 1).…”

“…The recovery of nucleated cells was 76.6 f 13.5 % (mean k SD). The suspension was homogenized, freeze-thawed 3 times and then sonicated for 30 s, 45-90 p1 of this cell lysate were used for determination of ALA synthase activity using as substrate 1.4-14C-succinate as described by Fraser & Schachter (1980). Duplicate incubations (37"C, 30 min) were carried out for each subject in the presence of varying amounts of pyridoxal-5-phosphate (0 to 1 mmol/l).…”

The effects of ethanol and anticonvulsants on erythroid δ‐aminolaevulinic acid synthase

“…The evidence for reduced availability of PLP in alcoholics is conflicting; whereas some workers have found reduced levels of PLP in alcoholics due either to reduced synthesis or increased degradation (13,14) others have reported normal levels (15). Fraser & Schacter (10) found that in their alcoholic patients there was no difference from controls in the effect of adding PLP on ALA-synthase activity, and our results support their observations. In only 1 of our patients was t h y e a marked increase in activity on addition of PLP.…”

Abnormal haem biosynthesis in chronic alcoholics

“…Both these enzymes had been noted to be depressed by acute alcohol ingestion, and it is likely that in certain patients this persists with chronic alcohol ingestion resulting in alcohol-induced anaemia. Patients with alcohol-related sideroblastic anaemia have increased bone marrow ALA synthase, accumulation of protoporphyrin and coproporphyrin in erythrocytes and accumulation of non-haem iron [ 18,191. All these features are explained by depressed activity of coproporphyrinogen oxidase and ferrochelatase.…”