British Journal of Haematology. 1986, 64, 415-418

Annotation

PRIMARY ACQUIRED SIDEROBLASTIC ANAEMIA

The original desfiption of iron-containing granules in human erythroid cells (Gruneberg, 1941; Doniach et al, 1943; Douglas & Dacie, 1953) was followed by an account of refractory anaemia with a sideroblastic bone marrow (Bjorkman, 1956). The numerous varieties of sideroblastic anaemia were subsequently discussed in a symposium on the subject published in this Journal in January 1965 and were reviewed more recently by Bottomley (1982). Primary acquired sideroblastic anaemia (PASAFalso known as idiopathic acquired sideroblastic anaemia or refractory anaemia with ring sideroblasts-emerges as a distinct clinical syndrome unrelated either to the congenital forms of sideroblastic anaemia or sideroblastic erythropoiesis secondary to other disorders. Despite the considerable literature there are stii some questions regarding the nature of the condition and the reason for the peculiar erythroid appearances.

What is a sideroblast?

Normal human erythroblasts may contain up to four randomly located iron containing granules in their cytoplasm (Bainton & Finch, 1964). Electron microscopy shows these to be small aggregates of iron-loaded ferriti molecules, sometimes surrounded by a membrane. About 40-60% of normoblasts have cytoplasmic iron detectable by Perls reaction. An increase, both in the number and in the size, of extra-mitochondria1 ferritin aggregates may be found in a wide variety of abnormal haematological states, including haemolytic disorders, pernicious anaemia and the haemoglobinopathies. These aggregates do not qualify the cells as sideroblasts. On the other hand, we designate as ring sideroblasts those erythroid cells in which the iron granules are seen mostly adjacent to the nucleus. Ultrastructural analysis has shown that these cells have intramitochondrial deposits of amorphous insoluble iron quite distinct from ferritin (Bessis & Jensen, 1965). Erythroblasts showing this phenomenon invariably have a coexistent increase in cytoplasmic ferritin aggregates (May et d, 1982).

What causes mitochondrial iron deposition?

It has been generally held that mitochondrial iron deposits are secondary to a failure of haem synthesis and there is a considerable literature showing defects in this synthetic pathway (Bottomley, 1982). The deficiency of haem synthesis in patients with idiopathic sideroblastic anaemia has also been thought to cause a secondary inhibition of globin synthesis (White & Hornrand, 19 74) as well as an increased uptake of iron by immature erythroid cells (Ponka & Neuwirt, 1974).

Correspondence: Professor AUan Jacobs, Department of Haematology, Welsh National School of Medicine, Heath Park, Cardiff CP4 4XW.

41 5

416 Annotation

More recent evidence suggests an alternative view. Severe haem synthesis deficiency has been documented in a number of instances without coexistent sideroblast formation. In hereditary bovine protoporphyria there is a ‘total body’ deficiency of ferrochelatase in which red cell protoporphyrin concentrations may be more than 200 times normal (Schwartz et al, 1978) but no sideroblasts are found. Stavem et al(1985) have documented two sisters with congenital hypochromic anaemia associated with erythroid ferrochelatase deficiency in neither of whom was there any evidence of sideroblastic change in the bone marrow. Romslo et al(1982) reported an interesting patient with idiopathic sideroblastic anaemia who had greatly increased levels of erythrocyte and plasma protoporphyrin with both mitochondrial and lysosomal iron deposits in nearly all erythroblasts. While the erythrocyte protoporphyrin concentration was over 100 times normal, metal chelatase activity was found to be normal when using cobalt as the substrate. These authors suggested that since their patient had a normal metal chelatase activity, erythrocyte protoporphyrin may have accumulated because of a reduced availability of ferrous iron for the enzyme. The insertion of iron into protoporphyrin by mitochondrial ferrochelatase requires an energy dependent transport of ferrous iron to within the mitochondria, and it is suggested that a primary mitochondrial lesion may impair the maintenance of iron in the reduced state resulting in precipitation and consequent unavailability to the enzyme.

May et al (1982) have shown that iron uptake by erythroblasts in sideroblastic bone marrow is essentially normal, though there is a decreased incorporation into haem and an increased incorporation into the cell stroma. Stromal iron incorporation was high at all stages of differentiation, even in the earliest erythroblasts which do not normally show any haem synthetic activity. This supports the suggestion that the primary defect in idiopathic sideroblastic anaemia may be an abnormality of mitochondrial iron metabolism rather than an abnormality of haem synthesis. It is not difticult to imagine that such intramitochondrial iron accumulation would readily give rise to increased free radical formation and the consequent lipid and protein damage would result in serious disruption of mitochondrial function, The observation of Aoki (1980) that multiple mitochondrial enzyme defects occur in patients with idiopathic sideroblastic anaemia, including some that do not directly involve haem synthesis, might be considered supportive of this hypothesis.

The characteristic iron loaded mitochondria of erythroid cells in primary acquired sideroblastic anaemia (PASA) are usually accompanied by nuclear abnormalities and ineffective erythropiesis. Wickrarnasinghe et al(1968) have shown gross abnormalities of cell proliferation and protein synthesis in these cells. Resting cells with iron loaded mitochondria do not enter S phase and those S phase cells which accumulate iron appear to be arrested in mid-cycle or G2.

What is primary acquired sideroblastic anaemia? Dameshek (1965) considered the possibility that sideroblastic anaemia is a malignancy. Cheng et al(1979) reviewed 268 cases reported in the literature and found a 10% overall incidence of acute leukaemic transformation. More recent estimates on smaller groups of patients have given varying figures for the incidence of leukaemic change and Kitahara et al (1980) reported a case which they attributed to the secondary effects of chemotherapy for

Annotation 41 7 Hodgkin’s disease. More recently the condition has been included amongst the myelodysplas- tic syndromes (Bennett et al, 1982) and there is little doubt that it represents a clonal abnormality of the haemopoietic stem cell characterized by a very specific phenotypic abnormality in which the characteristic mitochondrial changes are accompanied by erythroid hyperplasia in the bone marrow and grossly ineffective erythropoiesis (Jacobs, 1985). The clonal nature of the disorder has been well demonstrated in a case report by Prchal et a1 (1978) in which a black woman with PASA, apparently affecting only the erythroid cells, was found to be heterozygous for the G6PD isoenzymes. While both fibroblasts and salivary gland cells contained both isoenzymes, only a single type was found in red cells, neutrophils, platelets, T-cells and B-cells. In many patients a clonal karyotype abnormality is present.

Myelodysplastic marrows may contain 1-88% sideroblasts (Juneja et d, 1983; May et al, 1985) and the arbitrary designation of only those with over 15% sideroblasts as PASA as suggested in the FAB classification (Bennett et al, 1982) is, perhaps, a little rigid. However, those patients with a high sideroblast count undoubtedly have a relatively good prognosis compared with other myelodysplastic states and this may be associated with a higher modal value of DNA content (Clark et al, 1986) and the relative infrequency of chromosome deletions, particularly monosomy 7 (Knapp et d, 1985).

PASA may represent an early stage in a progressive preleukaemic evolution of the haemopoietic stem cell (Jacobs, 1985). Ferrokinetic studies have already shown that those preleukaemic patients with the greatest degree of erythroid hyperplasia and ineffective erythropoiesis are usually sideroblastic and have the longest survival (Cazzola et al, 1982). Ineffective erythropoiesis is also one of the earliest signs of myelodysplasia (May et al, 1985). Fohlmeister et ul(198 5) have suggested that patients with myelodysplastic syndromes evolve through a number of stages characterized by differences in bone marrow morphology with erythroid hyperplasia preceding the myeloid hyperplasia found in refractory anaemias, again indicating that PASA may represent an early phase in haematological malignancy.

The recognition that PASA represents a variant of the disordered haemopoietic proliferation that characterizes the preleukaemic state does not explain why this erythroid hyperplasia dominates the clinical picture in the early stages of the process. Nor does it explain the mechanism of mitochondrial damage. It does, however, suggest that the nuclear abnormalities so long noted as an accompaniment to sideroblastic change may reflect the primary disorder of growth control and the mitochondrial lesions may be a secondary phenomenon.

Department of Haematology, Welsh National School of Medicine, Cardiff

ALLAN JACOBS

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